Novel benzenesulfonamides as calcium channel blockers

ABSTRACT

The present application relates to calcium channel inhibitors comprising compounds of formula (I), formula (II), formula (III), or formula (IV), 
     
       
         
         
             
             
         
       
     
     wherein L 1 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7  and R c  are as defined in the specification. The present application also relates to compositions comprising such compounds, and methods of treating conditions and disorders using such compounds and compositions.

CROSS REFERENCE SECTION TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/323,029, filed on Dec. 12, 2011, which claims priority to U.S. patentapplication Ser. No. 12/687,465, filed on Jan. 14, 2010, which claimspriority to U.S. patent application Ser. No. 61/144,899, filed Jan. 15,2009, all of which are incorporated herein by reference in theirentirety.

TECHNICAL FIELD

The present invention relates to compounds that are calcium channelblockers, compositions including such compounds, and methods of treatingconditions and disorders using such compounds and compositions.

BACKGROUND OF THE INVENTION

Voltage-gated calcium channels (VGCC) play an integral role in theregulation of membrane ion conductance, neurotransmitter release, andcellular excitability. VGCC are composed of the pore-forming α1 subunitand auxiliary α2δ and β subunits that modulate channel expression andfunctional properties (Dolphin, A. C. A short history of voltage-gatedcalcium channels. British Journal of Pharmacology 2006, 147 (Suppl. 1),S56-S62.). These channels can be classified into low-voltage activated(LVA; T-type or Ca_(v)3.x) and high-voltage activated (HVA; L-type orCa_(v)1.x and N-, P/Q- and R-types or Ca_(v)2.x) channels. N-, P/Q and Rchannels typically activate at more positive membrane potentials (˜−30mV) and are involved in “presynaptic” neurotransmission (McGivern J. G.Targeting N-type and T-type calcium channels for the treatment of pain.Drug Discovery Today 2006, 11, 245-253.). T-type channels are activatedat relatively negative membrane potentials (˜−60 mV) and are primarilyinvolved in “postsynaptic” excitability (Shin, H.-S.; et al. T-type Ca²⁺channels as therapeutic targets in the nervous system. Curr. Opin. inPharmacology 2008, 8, 33-41.).

N-type channel α_(δ) subunits are encoded by a single gene (α₁B orCa_(v)2.2) in contrast to pharmacologically defined L- and T-typecurrents that are encoded by multiple α₁-subunit genes. A diversity ofN-type channels arises due to extensive alternative splicing of the αsubunit gene that generates variants with different expression patternsand GPCR-modulated biophysical properties (Gray, A. C.; et al. Neuronalcalcium channels: splicing for optimal performance. Cell Calcium, 2007,42(4-5), 409-417.). The primary sequence for Ca_(v)2.2 is highlyconserved across species (rat and human share 91% identity at the aminoacid level).

N-type channels are widely expressed in the central nervous system (CNS)(cortex, hippocampus, striatum, thalamus, brain stem nuclei and spinalcord) and in the peripheral nervous system (PNS) (adult sympatheticnervous system and dorsal root ganglia) (Ino, M.; et al. Functionaldisorders of the sympathetic nervous system in mice lacking the α_(1B)subunit (Ca_(v)2.2) of N-type calcium channels. Proc. Natl. Acad. Sci.USA 2001, 98(9), 5323-5328). In pain pathways, N-type channels areexpressed in the rostral ventral medulla, an important site ofdescending pain modulation (Urban, M. O.; et al. Medullary N-type andP/Q-type calcium channels contribute to neuropathy-induced allodynia.Neuroreport 2005, 16(6), 563-566.) and are a major contributor to thesynaptic neurotransmission that occurs between C/Aδ nociceptors andspinal lamina I neurons (Bao, J.; et al. Differences in Ca²⁺ channelsgoverning generation of miniature and evoked excitatory synapticcurrents in spinal laminae I and II. J. Neurosci. 1998, 18(21), 8740-50.Heinke, B.; et al. Pre- and postsynaptic contributions ofvoltage-dependent Ca²⁺ channels to nociceptive transmission in ratspinal lamina I neurons. Eur. J. Neurosci. 2004, 19(1), 103-111.). Incontrast, P/Q type channels are expressed almost exclusively in laminaeII-IV of the spinal cord and show little co-localization with SubstanceP and N-type channels (Westenbroek, R. E.; et al. Localization of Ca²⁺channel subtypes on rat spinal motor neurons, interneurons, and nerveterminals. J. Neurosci. 1998, 18(16), 6319-6330.).

Following nerve injury there is increased expression of Ca_(v)2.2(Westenbroek, R. E.; et al. Localization of Ca²⁺ channel subtypes on ratspinal motor neurons, interneurons, and nerve terminals. J. Neurosci.1998, 18(16), 6319-6330. Cizkova, D.; et al. Localization of N-type Ca²⁺channels in the rat spinal cord following chronic constrictive nerveinjury. Exp. Brain Res. 2002, 147, 456-463. Yokoyama, K.; et al. Plasticchange of N-type calcium channel expression after preconditioning isresponsible for prostaglandin E2-induced long-lasting allodynia.Anesthesiology 2003, 99(6), 1364-1370.) and α2δ1 subunits (Luo, Z. D.;et al. Upregulation of dorsal root ganglion α2δ calcium channel subunitand its correlation with allodynia in spinal nerve-injured rats. J.Neurosci. 2001, 21(6), 1868-1875. Newton, R. A.; et al. Dorsal rootganglion neurons show increased expression of the calcium channel α2δ-1subunit following partial sciatic nerve injury. Mol. Brain. Res. 2001,95(1-2), 1-8.) in addition to increases in the superficial layers of thedorsal horn of the spinal cord supporting a role for N-type channels inneuropathic pain. Recently a nociceptor-specific Ca_(v)2.2 splicevariant has been identified in the dorsal root ganglion (Bell, T. J.; etal. Cell specific alternative splicing increases calcium channel densityin the pain pathway. Neuron 2004, 41(1), 127-138.). These channels havedistinct electrophysiological properties and current densities(Castiglioni, A. J.; et al. Alternative splicing in the C-terminus ofCa_(v)2.2 controls expression and gating of N-type calcium channels. J.Physiol. 2006, 576(Pt 1), 119-134.) compared to wild-type Ca_(v)2.2channels. While G-protein coupled receptor inhibition of wildtype N-typechannels is typically mediated by Gβγ and is voltage-dependent, thenociceptor specific splice variant is inhibited by GPCR activation (e.g.opioids) in a voltage-independent fashion (Raingo, J.; et al.Alternative splicing controls G protein-dependent inhibition of N-typecalcium channels in nociceptors. Nat. Neurosci. 2007, 10(3), 285-292.).This mechanism substantially increases the sensitivity of Ca_(v)2.2channels to opiates and gamma-aminobutyric acid (GABA) suggesting thatcell-specific alternative splicing of mRNA for Ca_(v)2.2 channels servesas a molecular switch that controls the sensitivity of N-type channelsto neurotransmitters and drugs that modulate nociception. Collectivelythese data provide further support for the role of Ca_(v)2.2 channels inpain states.

The relative contributions of various HVA Ca²⁺ channels in nociceptivesignaling have been evaluated using knockout mice studies. Ca_(v)2.2knockout mice are healthy, fertile, and do not display overtneurological deficits (Ino, M.; et al. Functional disorders of thesympathetic nervous system in mice lacking the alpha 1B subunit(Ca_(v)2.2) of N-type calcium channels. Proc. Natl. Acad. Sci. USA 2001,98(9), 5323-5328. Kim, C.; et al. Altered nociceptive response in micedeficient in the alpha_(1B) subunit of the voltage-dependent calciumchannel. Mol. Cell. Neurosci. 2001, 18(2), 235-245. Hatakeyama, S.; etal. Differential nociceptive responses in mice lacking the alpha_(1B)subunit of N-type Ca²⁺ channels. Neuroreport 2001, 12(11), 2423-2427.Liu; L.; et al. In vivo analysis of voltage-dependent calcium channels.J. Bioenerg. Biomembr. 2003, 35(6), 671-685.). This finding suggeststhat other types of Ca_(v) channels are able to compensate for the lackof Ca_(v)2.2 channels at most synapses in these mice (Pietrobon, D.Function and dysfunction of synaptic calcium channels: insights frommouse models. Curr. Opin. Neurobiol. 2005, 15(3), 257-265.). Ca_(v)2.2deficient mice are resistant to the development of inflammatory andneuropathic pain (Kim, C.; et al. Altered nociceptive response in micedeficient in the alpha_(1B) subunit of the voltage-dependent calciumchannel. Mol. Cell. Neurosci. 2001, 18(2), 235-245. Hatakcyama, S.; etal. Differential nociccptivc responses in mice lacking the alpha_(1B)subunit of N-type Ca²⁺ channels. Neuroreport 2001, 12(11), 2423-2427.Saegusa, H.; et al. Suppression of inflammatory and neuropathic painsymptoms in mice lacking the N-type calcium channel. EMBO J. 2001,20(10), 2349-2356.), have decreased sympathetic nervous system functionOno, M.; et al. Functional disorders of the sympathetic nervous systemin mice lacking the alpha 1B subunit (Ca_(v)2.2) of N-type calciumchannels. Proc. Natl. Acad. Sci. USA 2001, 98(9), 5323-5328.), andaltered responses to both ethanol and anesthetics (Newton, R. A.; et al.Dorsal root ganglion neurons show increased expression of the calciumchannel alpha2delta-1 subunit following partial sciatic nerve injury.Brain Res. Mol. Brain. Res. 2001, 95(1-2), 1-8. Takei, R. et al.Increased sensitivity to halothane but decreased sensitivity to propofolin mice lacking the N-type Ca²⁺ channel. Neurosci. Lett. 2003, 350(1),41-45.). Additional behavioral studies indicate that Ca_(v)2.2 knockoutmice are less anxious, are hyperactive, and show enhanced vigilancecompared to wild-type littermates (Beuckmann, C. T.; et al. N-typecalcium channel alpha_(1B) subunit (Ca_(v)2.2) knock-out mice displayhyperactivity and vigilance state differences. J. Neurosci. 2003,23(17), 6793-6797.).

N- and P/Q-type channels are localized at neuronal synaptic junctionsand contribute significantly to neurotransmitter release (Olivera, B.M.; et al. Calcium channel diversity and neurotransmitter release: theomega-conotoxins and omega agatoxins. Annu Rev. Biochcm. 1994, 63,823-867. Miljanich, G. P.; et al. Antagonists of neuronal calciumchannels: structure, function, and therapeutic implications. Annu. Rev.Pharmacol. Toxicol. 1995, 35, 707-734.). N-type channels play a majorrole in the release of glutamate, acetylcholine, dopamine,norepinephrine, GABA and calcitonin gene-related protein (CGRP).P/Q-type channels may be involved in the release of glutamate,aspartate, 5HT, GABA and probably glycine (Pietrobon, D. Function anddysfunction of synaptic calcium channels: insights from mouse models.Curr. Opin. Neurobiol. 2005, 15(3), 257-265.).

L, P/Q and N-type channels are blocked by channel specific antagonistsi.e., dihydropyridines, ω-agatoxin IVA and ω-conotoxin MVIIA/ziconotide,respectively. Agatoxin IVa has been shown to block excitatory (Luebke,J. I.; et al. Multiple calcium channel types control glutamatergicsynaptic transmission in the hippocampus. Neuron 1993, 11(5), 895-902.)as well as inhibitory neurotransmission (Takahashi, T.; et al. Differenttypes of calcium channels mediate central synaptic transmission. Nature1993, 366(6451), 156-158.). Intrathecal injection of selective N-typechannel blockers (e.g. conotoxin-derived peptides such as GVIA, MVIIA(ziconotidc), and CVID) significantly attenuates pain responses inanimal models of neuropathic pain, formalin-induced pain, andpost-operative pain (Chaplan, S. R.; et al. Role of voltage-dependentcalcium channel subtypes in experimental tactile allodynia. J.Pharmacol. Exp. Ther. 1994, 269(3), 1117-1123. Malmberg, A. B.; et al.Voltage-sensitive calcium channels in spinal nociceptive processing:blockade of N- and P-type channels inhibits formalin-inducednociception. J. Neurosci. 1994, 14(8), 4882-4890. Bowersox, S. S.; etal. Selective N-type neuronal voltage-sensitive calcium channel blocker,SNX-111, produced spinal antinociception in rat models of acute,persistent and neuropathic pain. J. Pharmacol. Exp. Ther. 1996, 279(3),1243-1249. Wang, Y. X.; et al. Effects of intrathecal administration ofziconotide, a selective neuronal N-type calcium channel blocker, onmechanical allodynia and heat hyperalgesia in a rat model ofpostoperative pain. Pain 2000, 84(2-3), 151-158. Scott, D. A.; et al.Actions of intrathecal omega-conotoxins CVID, GVIA, MVIIA, and morphinein acute and neuropathic pain in the rat. Eur. J. Pharmacol. 2002,451(3), 279-286.). These peptide blockers bind to the pore region of thechannel, do not show voltage- or frequency-dependent activity, and showirreversible channel block (Feng, Z. P.; et al. Determinants ofinhibition of transiently expressed voltage-gated calcium channels byomega-conotoxins GVIA and MVIIA. J. Biol. Chem. 2003, 278(22),20171-20178.). Ziconotide potently blocks neurotransmitter release inthe spinal cord dorsal horn (Matthews, E. A.; et al. Effects of spinallydelivered N- and P-type voltage-dependent calcium channel antagonists ondorsal horn neuronal responses in a rat model of neuropathy. Pain 2001,92(1-2), 235-246. Smith, M. T.; et al. The novel N-type calcium channelblocker, AM336, produces potent dose-dependent antinociception afterintrathecal dosing in rats and inhibits substance P release in ratspinal cord slices. Pain 2002, 96(1-2), 119-127. Heinke, B.; et al. Pre-and postsynaptic contributions of voltage-dependent Ca²⁺ channels tonociceptive transmission in rat spinal lamina I neurons. Eur. J.Neurosci. 2004, 19(1), 103-111.) and in dorsal root ganglion (DRG)neurons (Evans, A. R.; et al. Differential regulation of evoked peptiderelease by voltage-sensitive calcium channels in rat sensory neurons.Brain Res. 1996, 712(2), 265-273. Smith, M. T.; et al. The novel N-typecalcium channel blocker, AM336, produces potent dose-dependentantinociception after intrathecal dosing in rats and inhibits substanceP release in rat spinal cord slices. Pain 2002, 96(1-2), 119-127.). Italso potently and fully blocks depolarization-induced release ofsubstance P from rat spinal cord slices. In contrast, intrathecaldelivery of the selective P/Q type blocker ω-agatoxin IVA had no effectson mechanical allodynia in the spinal nerve ligation model (Chaplan, S.R.; et al. Role of voltage-dependent calcium channel subtypes inexperimental tactile allodynia. J. Pharmacol. Exp. Ther. 1994, 269(3),1117-1123.) or thermal hyperalgesia in the chronic constriction injurymodel (Yamamoto, T.; et al. Differential effects of intrathecallyadministered N- and P-type voltage-sensitive calcium channel blockersupon two models of experimental mononeuropathy in the rat. Brain Res.1998, 794(2), 329-332.) of neuropathic pain.

Accordingly, since pain is the most common symptom of disease and themost frequent complaint with which patients present to physicians, thereis a need for compounds, such as those of the present invention, thatare novel calcium channel blockers that have a utility in treating pain,amongst other conditions.

SUMMARY OF THE INVENTION

The invention is directed to compounds of formula (I) or formula (II)

or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or acombination thereof, wherein

one of R¹ and R² is X, and the other of R¹ and R² is Y;

X is (i) or (ii);

-   -   m and n, at each occurrence, are independently 1 or 2;    -   G¹ is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl,        thiomorpholinyl or azepanyl, wherein G¹ is connected through the        nitrogen atom of said azetidinyl, pyrrolidinyl, piperidinyl,        morpholinyl, thiomorpholinyl or azepanyl;

Y is —NR^(c)Ar¹, —NR^(c)Ar²—Ar¹, —NR^(c)CH(Ar¹)₂,—NR^(c)(CR^(a)R^(b))_(p)Ar¹, —NR^(c)(CR^(a)R^(b))_(p)CH(Ar¹)₂,—NR^(c)-G², —NR^(c)-G²-Ar¹, (iii), (iv), (v) or (vi);

-   -   Ar¹, at each occurrence, is independently aryl or heteroaryl,        wherein said aryl and heteroaryl are unsubstituted or        substituted with 1, 2, 3, or 4, or 5 substituents selected from        alkoxy, alkyl, cyano, haloalkyl, halogen, or —N(alkyl)₂;    -   Ar^(e) is aryl or heteroaryl, wherein said aryl and heteroaryl        are unsubstituted or substituted with 1, 2, 3, or 4 substituents        selected from alkoxy, alkyl, cyano, haloalkyl, or halogen;    -   G² is cycloalkyl;    -   R^(a) and R^(b) are at each occurrence independently hydrogen,        alkyl, or hydroxyalkyl;    -   R^(c) is hydrogen or alkyl;    -   p is 1, 2, 3, or 4; and

R³, R⁴, R⁵ and R⁶ are each independently hydrogen, alkoxy, alkyl, orhalogen.

The invention is also directed to compounds of formula (III) or formula(IV)

or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or acombination thereof, wherein

L¹ is C(O) or S(O)₂;

R² is X;

X is (i) or (ii);

-   -   m and n, at each occurrence, are independently 1 or 2;    -   G¹ is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl,        thiomorpholinyl or azepanyl, wherein G¹ is connected through the        nitrogen atom of said azetidinyl, pyrrolidinyl, piperidinyl,        morpholinyl, thiomorpholinyl or azepanyl;

R³, R⁴, R⁵ and R⁶ are each independently hydrogen, alkoxy, alkyl, orhalogen;

R⁷ is S(O)₂Ar³, —C(O)Ar³, S(O)₂(CR^(a)R^(b))_(p)Ar³,—C(O)(CR^(a)R^(b))_(p)Ar³, —S(O)₂(CR^(a)R^(b))_(p)CH(Ar³)₂,—C(O)(CR^(a)R^(b))_(p)CH(Ar³)₂, —C(O)CH(Ar³)₂, or —CH(Ar³)₂;

-   -   Ar³, at each occurrence, is aryl or heteroaryl, wherein said        aryl and heteroaryl are unsubstituted or substituted with 1, 2,        3, 4, or 5 substituents selected from alkoxy, alkyl, cyano,        haloalkyl, or halogen;

R^(a) and R^(b) are at each occurrence independently hydrogen, alkyl, orhydroxyalkyl;

-   -   p is 1, 2, 3, or 4; and

R^(c) is hydrogen or alkyl.

Another aspect of the invention relates to pharmaceutical compositionscomprising a therapeutically effective amount of compound(s) of theinvention or pharmaceutically acceptable salts thereof, in combinationwith one or more pharmaceutically acceptable carriers. Such compositionscan be administered in accordance with a method of the invention,typically as part of a therapeutic regimen for treatment or preventionof conditions and disorders related to calcium channels. Moreparticularly, the method is useful for treating conditions related to amethod of treating pain in a subject in need thereof. The methodcomprises administering to the subject a therapeutically suitable amountof a compound of formula (I), or a pharmaceutically acceptable saltthereof. Conditions related to pain include acute pain, chronic pain,neuropathic pain, inflammatory pain, visceral pain, cancer pain,allodynia, fibromyalgia, sciatica, back pain, and headache painincluding migraine, or combinations thereof.

Another aspect of the invention provides a method of treating disordersof the central nervous system in a subject in need thereof. The methodcomprising the step of: administering a therapeutically suitable amountof a compound of formula (I), or a pharmaceutically acceptable saltthereof. The disorders of the central nervous system include stroke,epilepsy, manic depression, bipolar disorders, depression, anxiety,schizophrenia, migraine, and psychoses; neural degenerative disordersincluding Alzheimer's disease, AIDS related dementia, Parkinson'sdisease, neuropathy caused by head injury, and dementia caused bycerebrovascular disorders; disorders of the lower urinary tractincluding overactive bladder, prostatis, prostadynia, interstitialcystitis, and benign prostatic hyperplasia; disorders caused bypsychogenic stress including bronchial asthma, unstable angina, andhypersensitive colon inflammation; cardiovascular disorders includinghypertension, atherosclerosis, heart failure, and cardiac arrhythmias;drug addiction withdrawal symptoms, including ethanol addictionwithdrawal symptoms; skin disorders including pruritis and allergicdermatitis, inflammatory bowel disease; cancer; diabetes; andinfertility and sexual dysfunction, or combinations thereof.

The compounds, compositions comprising the compounds, and methods fortreating or preventing conditions and disorders by administering thecompounds are further described herein.

DETAILED DESCRIPTION OF THE INVENTION

Compounds of formula (I), formula (II), formula (III), or formula (IV)are disclosed in this invention

wherein L¹, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R^(c) are as defined abovein the Summary of the Invention. Compositions comprising such compoundsand methods for treating conditions and disorders using such compoundsand compositions are also disclosed.

In various embodiments, the present invention provides at least onevariable that occurs more than one time in any substituent or in thecompound of the invention or any other formulae herein. Definition of avariable on each occurrence is independent of its definition at anotheroccurrence. Further, combinations of substituents are permissible onlyif such combinations result in stable compounds. Stable compounds arecompounds, which can be isolated from a reaction mixture.

a. DEFINITIONS

As used in the specification and the appended claims, unless specifiedto the contrary, the following terms have the meaning indicated:

The term “alkoxy” as used herein means an alkyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of alkoxy include, but are not limited to,methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, andhexyloxy.

The term “alkyl” as used herein, means a straight or branched, saturatedhydrocarbon chain containing from 1 to 10 carbon atoms. The term “loweralkyl” or “C₁₋₆ alkyl” means a straight or branched chain hydrocarboncontaining 1 to 6 carbon atoms. The term “C₁₋₃ alkyl” means a straightor branched chain hydrocarbon containing 1 to 3 carbon atoms.

Representative examples of alkyl include, but are not limited to,methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,tort-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, andn-decyl.

The term “alkylene” means a divalent group derived from a straight orbranched chain hydrocarbon of from 1 to 10 carbon atoms. Representativeexamples of alkylene include, but are not limited to, —CH₂—, —CH(CH₃)—,—C(CH₃)₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, and —CH₂CH(CH₃)CH₂—.

The term “aryl” as used herein, means phenyl or a bicyclic aryl. Thebicyclic aryl is naphthyl, or a phenyl fused to a monocyclic cycloalkyl,or a phenyl fused to a monocyclic cycloalkenyl. Representative examplesof the bicyclic aryl groups include, but are not limited to,dihydroindenyl, indenyl, naphthyl, dihydronaphthalenyl, andtetrahydronaphthalenyl. The bicyclic awl is attached to the parentmolecular moiety through any carbon atom contained within the bicyclicring system. The aryl groups of the present invention can beunsubstituted or substituted.

The term “arylalkyl” as used herein, means an aryl group, as definedherein, appended to the parent molecular moiety through an alkylenegroup, as defined herein. Representative examples of arylalkyl include,but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and2-naphth-2-ylethyl.

The term “cyano” as used herein, means a —CN group.

The term “cycloalkyl” or “cycloalkane” as used herein, means amonocyclic, a bicyclic, or a tricyclic cycloalkyl. The monocycliccycloalkyl is a carbocyclic ring system containing three to eight carbonatoms, zero heteroatoms and zero double bonds. Examples of monocyclicring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl. The bicyclic cycloalkyl is a monocycliccycloalkyl fused to a monocyclic cycloalkyl ring, or a bridgedmonocyclic ring system in which two non-adjacent carbon atoms of themonocyclic ring are linked by an alkylene bridge containing one, two,three, or four carbon atoms. Representative examples of bicyclic ringsystems include, but are not limited to, bicyclo[3.1.1]heptane,bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane,bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane. Tricyclic cycloalkylsare exemplified by a bicyclic cycloalkyl fused to a monocycliccycloalkyl, or a bicyclic cycloalkyl in which two non-adjacent carbonatoms of the ring systems are linked by an alkylene bridge of 1, 2, 3,or 4 carbon atoms. Representative examples of tricyclic-ring systemsinclude, but are not limited to, tricyclo[3.3.1.0^(3,7)]nonane(octahydro-2,5-methanopentalene or noradamantane), andtricyclo[3.3.1.1^(3,7)]decane (adamantane). The monocyclic, bicyclic,and tricyclic cycloalkyls can be unsubstituted or substituted, and areattached to the parent molecular moiety through any substitutable atomcontained within the ring system.

The term “halo” or “halogen” as used herein, means Cl, Br, I, or F.

The term “haloalkyl” as used herein, means an alkyl group, as definedherein, in which one, two, three, four, five or six hydrogen atoms arereplaced by halogen. Representative examples of haloalkyl include, butare not limited to, chloromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl,trifluoromethyl, difluoromethyl, pentafluoroethyl,2-chloro-3-fluoropentyl, and trifluoropropyl such as3,3,3-trifluoropropyl. The term “heteroaryl” as used herein, means amonocyclic heteroaryl or a bicyclic heteroaryl. The monocyclicheteroaryl is a five- or six-membered ring. The five-membered ringcontains two double bonds. The five-membered ring may contain oneheteroatom selected from O or S; or one, two, three, or four nitrogenatoms and optionally one oxygen or sulfur atom. The six-membered ringcontains three double bonds and one, two, three or four nitrogen atoms.Representative examples of monocyclic heteroaryl include, but are notlimited to, furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl,1,3-oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl,pyrrolyl, tetrazolyl, thiadiazolyl, 1,3-thiazolyl, thienyl, triazolyl,and triazinyl. The bicyclic heteroaryl consists of a monocyclicheteroaryl fused to a phenyl, or a monocyclic heteroaryl fused to amonocyclic cycloalkyl, or a monocyclic heteroaryl fused to a monocycliccycloalkenyl, or a monocyclic heteroaryl fused to a monocyclicheteroaryl, or a monocyclic heteroaryl fused to a monocyclicheterocycle. Representative examples of bicyclic heteroaryl groupsinclude, but are not limited to, benzofuranyl, benzothienyl,benzoxazolyl, benzimidazolyl, benzoxadiazolyl,6,7-dihydro-1,3-benzothiazolyl, imidazo[1,2-a]pyridinyl, indazolyl,indolyl, isoindolyl, isoquinolinyl, naphthyridinyl, pyridoimidazolyl,quinolinyl, thiazolo[5,4-b]pyridin-2-yl, thiazolo[5,4-d]pyrimidin-2-yl,and 5,6,7,8-tetrahydroquinolin-5-yl. The monocyclic and bicyclicheteroaryl groups of the present invention can be substituted orunsubstituted and are connected to the parent molecular moiety throughany carbon atom or any nitrogen atom contained within the ring systems.

The term “heterocycle” or “heterocyclic” as used herein, means amonocyclic heterocycle, a bicyclic heterocycle, or a tricyclicheterocycle. The monocyclic heterocycle is a three-, four-, five-, six-,seven-, or eight-membered ring containing at least one heteroatomindependently selected from the group consisting of O, N, and S. Thethree- or four-membered ring contains zero or one double bond, and oneheteroatom selected from the group consisting of O, N, and S. Thefive-membered ring contains zero or one double bond and one, two orthree heteroatoms selected from the group consisting of O, N and S. Thesix-membered ring contains zero, one or two double bonds and one, two,or three heteroatoms selected from the group consisting of O, N, and S.The seven- and eight-membered rings contains zero, one, two, or threedouble bonds and one, two, or three heteroatoms selected from the groupconsisting of O, N, and S. Representative examples of monocyclicheterocycles include, but are not limited to, azetidinyl, azepanyl,aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl,1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl,isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl,oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl,piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl,pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl,tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, 1,2-thiazinanyl,1,3-thiazinanyl, thiazolinyl, thiazolidinyl, thiomorpholinyl,1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, andtrithianyl. The bicyclic heterocycle is a monocyclic heterocycle fusedto a phenyl group, or a monocyclic heterocycle fused to a monocycliccycloalkyl, or a monocyclic heterocycle fused to a monocycliccycloalkenyl, or a monocyclic heterocycle fused to a monocyclicheterocycle, or a bridged monocyclic heterocycle ring system in whichtwo non adjacent atoms of the ring are linked by an alkylene bridge of1, 2, 3, or 4 carbon atoms, or an alkenylene bridge of two, three, orfour carbon atoms. Representative examples of bicyclic heterocyclesinclude, but are not limited to, benzopyranyl, benzothiopyranyl,chromanyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl,azabicyclo[2.2.1]heptyl (including 2-azabicyclo[2.2.1]hept-2-yl),2,3-dihydro-1H-indolyl, isoindolinyl, octahydrocyclopenta[c]pyrrolyl,octahydropyrrolopyridinyl, and tetrahydroisoquinolinyl. Tricyclicheterocycles are exemplified by a bicyclic heterocycle fused to a phenylgroup, or a bicyclic heterocycle fused to a monocyclic cycloalkyl, or abicyclic heterocycle fused to a monocyclic cycloalkenyl, or a bicyclicheterocycle fused to a monocyclic heterocycle, or a bicyclic heterocyclein which two non adjacent atoms of the bicyclic ring are linked by analkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridgeof two, three, or four carbon atoms. Examples of tricyclic heterocyclesinclude, but are not limited to, octahydro-2,5-epoxypentalene,hexahydro-2H-2,5-methanocyclopenta[b]furan,hexahydro-1H-1,4-methanocyclopenta[c]furan, aza-admantane(1-azatricyclo[3.3.1.1^(3,7)]decane), and oxa-adamantane(2-oxatricyclo[3.3.1.1^(3,7)]decane). The monocyclic, bicyclic, andtricyclic heterocycles are connected to the parent molecular moietythrough any carbon atom or any nitrogen atom contained within the rings,and can be unsubstituted or substituted.

The term “heteroatom” as used herein, means a nitrogen, oxygen, orsulfur atom.

The term “hydroxy” or “hydroxyl” as used herein, means an —OH group.

The term “hydroxyalkyl” as used herein means at least one hydroxy group,as defined herein, appended to the parent molecular moiety through analkyl group, as defined herein.

Representative examples of hydroxyalkyl include, but are not limited to,hydroxymethyl, 2-hydroxyethyl, 2-methyl-2-hydroxyethyl, 3-hydroxypropyl,2,3-dihydroxypentyl, and 2-ethyl-4-hydroxyheptyl.

b. COMPOUNDS

Compounds of the invention have the formula (I), formula (II), formula(III), or formula (IV) as described above.

Particular values of variable groups in compounds of formula (I),formula (II), formula (III), or formula (IV) are as follows. Such valuesmay be used where appropriate with any of the other values, definitions,claims or embodiments defined hereinbefore or hereinafter.

As described generally above for the compounds of formula (I) or formula(II), R¹ can be selected from X, wherein X is

m and n are independently 1 or 2; and G¹ is azetidinyl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl or azepanyl, wherein G¹ isconnected through the nitrogen atom of said azetidinyl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl or azepanyl.

Thus, compounds within formula (I) or formula (II) include compound ofthe following formula (V), formula (VI), formula (VII), or formula(VIII) and pharmaceutically acceptable salts thereof:

wherein R² is Y, and Y is selected from —NR^(c)Ar¹, —NR^(c)Ar²—Ar¹,—NR^(c)CH(Ar¹)₂, —NR^(c)(CR^(a)R^(b))_(p)Ar¹,—NR^(c)(CR^(a)R^(b))_(p)CH(Ar¹)₂, —NR^(c)-G², —NR^(c)-G²-Ar¹, (iii),(iv), (v) or (vi);

Ar¹, at each occurrence, is independently aryl or heteroaryl, whereinsaid aryl and heteroaryl are unsubstituted or substituted with 1, 2, 3,or 4, or 5 substituents selected from alkoxy, alkyl, cyano, haloalkyl,halogen, or —N(alkyl)₂; Ar² is aryl or heteroaryl, wherein said aryl andheteroaryl are unsubstituted or substituted with 1, 2, 3, or 4substituents selected from alkoxy, alkyl, cyano, haloalkyl, or halogen;G² is cycloalkyl; R^(a) and R^(b) are at each occurrence independentlyhydrogen, alkyl, or hydroxyalkyl; R^(c) is hydrogen or alkyl; p is 1, 2,3, or 4; and R³, R⁴, R⁵ and R⁶ are as disclosed in the Summary of theInvention and the embodiments described herein.

Other compounds formula (I) or formula (II) can include compoundswherein R² can be selected from X, wherein X is

m and n are independently 1 or 2; and G¹ is azetidinyl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl or azepanyl, wherein G¹ isconnected through the nitrogen atom of said azetidinyl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl or azepanyl.

Thus, compounds within formula (I) or formula (II) include compound ofthe following formula (IX), formula (X), formula (XI), or formula (XII)and pharmaceutically acceptable salts thereof:

wherein R¹ is Y, and Y is selected from —NR^(c)Ar¹, —NR^(c)Ar²—Ar¹,—NR^(c)CH(Ar¹)₂, —NR^(c)(CR^(a)R^(b))_(p)Ar¹,—NR^(c)(CR^(a)R^(b))_(p)CH(Ar¹)₂, —NR^(c)-G², —NR^(c)-G²-Ar¹, (iii),(iv), (v) or (vi);

Ar¹, at each occurrence, is independently aryl or heteroaryl, whereinsaid aryl and heteroaryl are unsubstituted or substituted with 1, 2, 3,or 4, or 5 substituents selected from alkoxy, alkyl, cyano, haloalkyl,halogen, or —N(alkyl)₂; Ar² is aryl or heteroaryl, wherein said aryl andheteroaryl are unsubstituted or substituted with 1, 2, 3, or 4substituents selected from alkoxy, alkyl, cyano, haloalkyl, or halogen;G² is cycloalkyl; R^(a) and R^(b) are at each occurrence independentlyhydrogen, alkyl, or hydroxyalkyl; R^(c) is hydrogen or alkyl; p is 1, 2,3, or 4; and R³, R⁴, R⁵ and R⁶ are as disclosed in the Summary of theInvention and the embodiments described herein.

As described generally above for the compounds of formula (III) orformula (IV), R² can be selected from X, wherein X is

m and n are independently 1 or 2; and G¹ is azetidinyl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl or azepanyl, wherein G¹ isconnected through the nitrogen atom of said azetidinyl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl or azepanyl.

Thus, compounds within formula (III) or formula (IV) include compound ofthe following formula (XIII), formula (XIV), formula (XV), or formula(XVI) and pharmaceutically acceptable salts thereof:

wherein L¹ is C(O) or S(O)₂; R⁷ is S(O)₂Ar³, —C(O)Ar³,—S(O)₂(CR^(a)R^(b))_(p)Ar³, —C(O)(CR^(a)R^(b))_(p)Ar³,—S(O)₂(CR^(a)R^(b))_(p)CH(Ar³)₂, —C(O)(CR^(a)R^(b))_(p)CH(Ar³)₂,—C(O)CH(Ar³)₂, or —CH(Ar³)₂; Ar^(a), at each occurrence, is aryl orheteroaryl, wherein said aryl and heteroaryl are unsubstituted orsubstituted with 1, 2, 3, 4, or 5 substituents selected from alkoxy,alkyl, cyano, haloalkyl, or halogen; R^(a) and R^(b) are at eachoccurrence independently hydrogen, alkyl, or hydroxyalkyl; p is 1, 2, 3,or 4; and R³, R⁴, R⁵, R⁶ and R^(c) are as disclosed in the Summary ofthe Invention and the embodiments described herein.

For each substructure wherein X is

and m and n are independently 1 or 2; there exist the followingembodiments which further define the scope of the compounds of thepresent invention. Accordingly, one aspect of the invention is directedto a group of substructures wherein X is formula (a), (b), (c), or (d).

For each substructure wherein X is

and G¹ is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl or azepanyl, wherein G¹ is connected through thenitrogen atom of said azetidinyl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl or azepanyl; there exist the followingembodiments which further define the scope of the compounds of thepresent invention. Accordingly, one aspect of the invention is directedto a group of substructures wherein X is formula (e), (f), (g), (h),(i), or (j).

As described generally above for the compounds of formula (I) or formula(II), one of R¹ and R² is selected from Y. Y is selected from—NR^(c)Ar¹, —NR^(c)Ar²—Ar¹, —NR^(c)CH(Ar¹)₂,—NR^(c)(CR^(a)R^(b))_(p)Ar¹, —NR^(c)(CR^(a)R^(b))_(p)CH(Ar¹)₂,—NR^(c)-G², —NR^(c)-G²-Ar¹, (iii), (iv), (v) or (vi);

Ar¹, at each occurrence, is independently aryl or heteroaryl, whereinsaid aryl and heteroaryl are unsubstituted or substituted with 1, 2, 3,or 4, or 5 substituents selected from alkoxy, alkyl, cyano, haloalkyl,halogen, or —N(alkyl)₂; Ar² is aryl or heteroaryl, wherein said aryl andheteroaryl are unsubstituted or substituted with 1, 2, 3, or 4substituents selected from alkoxy, alkyl, cyano, haloalkyl, or halogen;G² is cycloalkyl; p is 1, 2, 3, or 4.

In one embodiment, G² is cycloalkyl.

In another embodiment, G² is cyclopropyl.

In one embodiment, for compounds of formula (I), formula (II), formula(III) or formula (IV), R^(a) and R^(b) are at each occurrenceindependently hydrogen, alkyl, or hydroxyalkyl.

In another embodiment, for compounds of formula (I), formula (II),formula (III) or formula (IV), R^(a) and R^(b) are at each occurrenceindependently hydrogen or hydroxyalkyl.

In a further embodiment, for compounds of formula (I), formula (II),formula (III) or formula (IV), R^(a) and R^(b) are at each occurrencehydrogen.

In one embodiment, for compounds of formula (I), formula (II), formula(III) or formula (IV), R^(e) is hydrogen or alkyl.

In another embodiment, for compounds of formula (I), formula (II),formula (III) or formula (IV), R^(c) is hydrogen.

In a further embodiment, for compounds of formula (I), formula (II),formula (III) or formula (IV), R^(c) is alkyl.

In one embodiment for compounds of formula (I), formula (II), formula(III) or formula (IV), R³, R⁴, R⁵ and R⁶ are each independently selectedform hydrogen, alkoxy, alkyl, and halogen.

In another embodiment for compounds of formula (I), formula (II),formula (III) or formula (IV), two of R³, R⁴, R⁵ and R⁶ are halogen, andthe others are hydrogen.

In another embodiment for compounds of formula (I), formula (II),formula (III) or formula (IV), one of R³, R⁴, R⁵ and R⁶ are alkyl, andthe others are hydrogen.

In a further embodiment for compounds of formula (I), formula (II),formula (III) or formula (IV), one of R³, R⁴, R⁵ and R⁶ are halogen, andthe others are hydrogen.

In one embodiment for compounds of formula (III) or formula (IV), L¹ isC(O) or S(O)₂.

In another embodiment for compounds of formula (III) or formula (IV), L¹is C(O).

In a further embodiment for compounds of formula (III) or formula (IV),L¹ is S(O)₂.

In one embodiment for compounds of formula (III) or formula (IV), R⁷ isS(O)₂Ar³, —C(O)Ar³, S(O)₂(CR^(a)R^(b))_(p)Ar³,—C(O)(CR^(a)R^(b))_(p)Ar³, —S(O)₂(CR^(a)R^(b))_(p)CH(Ar³)₂,—C(O)(CR^(a)R^(b))_(p)CH(Ar³)₂, —C(O)CH(Ar³)₂, or —CH(Ar³)₂; wherein,Ar³, at each occurrence, is aryl or heteroaryl, wherein said aryl andheteroaryl are unsubstituted or substituted with 1, 2, 3, 4, or 5substituents selected from alkoxy, alkyl, cyano, haloalkyl, or halogen.

In another embodiment for compounds of formula (III) or formula (IV), R⁷is —S(O)₂Ar³, —C(O)Ar³, S(O)₂(CR^(a)R^(b))_(p)Ar³,—C(O)(CR^(a)R^(b))_(p)Ar³.

In a further embodiment, for compounds of formula (III) or formula (IV),R⁷ is —S(O)₂Ar³ or —C(O)Ar³.

In another embodiment for compounds of formula (III) or formula (IV), R⁷is —S(O)₂(CR^(a)R^(b))_(p)CH(Ar³)₂, —C(O)(CR^(a)R^(b))_(p)CH(Ar³)₂,—C(O)CH(Ar³)₂, or —CH(Ar³)₂.

In a further embodiment, for compounds of formula (III) or formula (IV),R⁷ is —C(O)CH(Ar³)₂, or —CH(Ar³)₂.

In one embodiment for compounds of formula (I) or formula (II), R¹ is X,wherein X is

R² is Y; and Y is —NR^(c)Ar¹. In another embodiment for compounds offormula (I), R¹ is X, wherein X is

n is 1; R² is Y; and Y is —NR^(c)Ar¹; Ar¹ is aryl; and R³, R⁴, R⁵ and R⁶are each independently hydrogen or halogen. In one embodiment forcompounds of formula (I) or formula (II), R¹ is X, wherein X is

n is 1; R² is Y; and Y is —NR^(c)CH(Ar¹)₂,—NR^(c)(CR^(a)R^(b))_(p)CH(Ar¹)₂, or (v).

In another embodiment for compounds of formula (I), R¹ is X, wherein Xis

n is 1; R² is Y; and Y is —NR^(c)CH(Ar¹)₂,—NR^(c)(CR^(a)R^(b))_(p)CH(Ar¹)₂, or (v);

R^(a) and R^(b) are at each occurrence hydrogen; R^(c) is hydrogen; p is1, 2 or 3; Ar¹, at each occurrence, is aryl; and R³, R⁴, R⁵ and R⁶ areeach independently hydrogen or halogen. In one embodiment for compoundsof formula (I) or formula (II), R¹ is X, wherein X is

n is 1; R² is Y; and Y is —NR^(c)Ar²—Ar¹, —NR^(c)(CR^(a)R^(b))_(p)Ar¹,—NR^(c)-G²-Ar¹, (iii), (iv), or (vi).

In another embodiment for compounds of formula (I), R¹ is X, wherein Xis

n is 1; R² is Y; and Y is —NR^(c)Ar²—Ar¹, —NR^(c)(CR^(a)R^(b))_(p)Ar¹,—NR^(c)-G²-Ar¹, (iii), (iv), or (vi);

R^(a) and R^(b) are, at each occurrence, independently hydrogen orhydroxyalkyl; R^(c) is hydrogen; p is 1, 2 or 3; Ar¹ is aryl; Ar² isaryl; G² is cyclopropyl; and R³, R⁴, R⁵ and R⁶ are each independentlyhydrogen or halogen. In a further embodiment for compounds of formula(II), R¹ is X, wherein X is

n is 1; R² is Y; and Y is —NR^(c)Ar²—Ar¹, —NR^(c)(CR^(a)R^(b))_(p)Ar¹,—NR^(e)-G²-Ar¹, (iii), (iv), or (vi);

R^(a) and R^(b) are, at each occurrence, independently hydrogen orhydroxyalkyl; R^(c) is hydrogen; p is 1, 2 or 3; Ar¹ is aryl; Ar² isaryl; G² is cyclopropyl; and R³, R⁴, R⁵ and R⁶ are each independentlyhydrogen or halogen.

In one embodiment for compounds of formula (I) or formula (II), whereinR¹ is X; and X is

In another embodiment for compounds of formula (I), wherein R¹ is X; andX is

G¹ is pyrrolidinyl or piperidinyl; R² is Y; Y is NR^(c)Ar¹; R^(c) ishydrogen; and Ar¹ is aryl, wherein said aryl is unsubstituted orsubstituted with 1, 2, or 3 substituents selected from haloalkyl andhalogen.

In one embodiment for compounds of formula (I) or formula (II), whereinR¹ is Y; Y is —NR^(c)CH(Ar¹)₂, —NR^(c)(CR^(a)R^(b))_(p)CH(Ar¹)₂, or (v);

R^(a) and R^(b) at each occurrence are independently hydrogen; R² is X;X is

and n is 1.

In another embodiment for compounds of formula (I), wherein R¹ is Y; Yis —NR^(c)CH(Ar¹)₂, —NR^(c)(CR^(a)R^(b))_(p)CH(Ar¹)₂, or (v);

Ar¹, at each occurrence, is independently aryl, wherein said aryl areunsubstituted or substituted with 1, 2, 3, or 4, or 5 substituentsselected from alkoxy, alkyl, cyano, haloalkyl, halogen, or —N(alkyl)₂;R^(a) and R^(b) at each occurrence are independently hydrogen; p is 1 or2; R² is X; X is

and n is 1; and R³, R⁴, R⁵ and R⁶ are each independently hydrogen orhalogen.

In one embodiment for compounds of formula (I) or formula (II), whereinR¹ is Y; Y is —NR^(c)Ar¹, —NR^(c)(CR^(a)R^(b))_(p)Ar¹, (iii), (iv), or(vi);

R² is X; and X is

In another embodiment for compounds of formula (I), wherein R¹ is Y; Yis —NR^(c)Ar¹, —NR^(c)(CR^(a)R^(b))_(p)Ar¹, —NR^(c)-G², or—NR^(c)-G²-Ar¹; R^(a) and R^(b) are independently, at each occurrence,hydrogen or hydroxyalkyl; p is 1, 2 or 3; Ar¹, at each occurrence, isindependently aryl, wherein said aryl are unsubstituted or substitutedwith 1, 2, 3, or 4, or 5 substituents selected from alkoxy, alkyl,cyano, haloalkyl, halogen, or —N(alkyl)₂; G² is cycloalkyl, whereincycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; R² isX; and X is

and R³, R⁴, R⁵ and R⁶ are each independently hydrogen or halogen.

In one embodiment for compounds of formula (III) wherein L¹ is C(O); R²is X; X is (i);

R⁷ is —S(O)₂Ar³, —C(O)Ar³, —S(O)₂(CR^(a)R^(b))_(p)Ar³, or—C(O)(CR^(a)R^(b))_(p)Ar³; and Ar^(a), at each occurrence, is aryl,wherein said aryl is unsubstituted or substituted with 1, 2, 3, 4, or 5substituents selected from alkoxy, alkyl, cyano, haloalkyl, or halogen.

In another embodiment for compounds of formula (IV) wherein L¹ is C(O);R² is X; X is (i);

R⁷ is —S(O)₂Ar³, —C(O)Ar³, S(O)₂(CR^(a)R^(b))_(p)Ar³, or—C(O)(CR^(a)R^(b))_(p)Ar³; and Ar³ is aryl, wherein said awl isunsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selectedfrom alkoxy, alkyl, cyano, haloalkyl, or halogen.

In another embodiment for compounds of formula (III) wherein L¹ is C(O);R² is X; X is (i);

R⁷ is —S(O)₂(CR^(a)R^(b))_(p)CH(Ar³)₂, —C(O)(CR^(a)R^(b))_(p)CH(Ar³)₂,—C(O)CH(Ar³)₂, or —CH(Ar³)₂; Ar³, at each occurrence, is aryl, whereinsaid aryl is unsubstituted or substituted with 1, 2, 3, 4, or 5substituents selected from alkoxy, alkyl, cyano, haloalkyl, or halogen;and p is 1, 2, or 3.

In another embodiment for compounds of formula (IV) wherein L¹ is C(O);R² is X; X is (i);

R⁷ is —S(O)₂(CR^(a)R^(b))_(p)CH(Ar³)₂, —C(O)(CR^(a)R^(b))_(p)CH(Ar³)₂,—C(O)CH(Ar³)₂, or —CH(Ar³)₂; Ar³, at each occurrence, is aryl, whereinsaid aryl is unsubstituted or substituted with 1, 2, 3, 4, or 5substituents selected from alkoxy, alkyl, cyano, haloalkyl, or halogen;and p is 1, 2, or 3.

Specific embodiments of compounds contemplated as part of the inventioninclude, but are not limited to:

-   3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]-N-[4-(trifluoromethyl)phenyl]benzenesulfonamide;-   N-(2-fluorophenyl)-3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;-   N-(3-fluorophenyl)-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;-   N-(2,6-difluorophenyl)-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;-   N-(4-fluorophenyl)-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;-   3-[(8 aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl    carbonyl]-N-[3-(trifluoromethyl)phenyl]benzenesulfonamide;-   N-(3-fluorophenyl)-3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2    (1H)-ylcarbonyl]benzenesulfonamide;-   3-[(8    aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]-N-[4-(trifluoromethyl)phenyl]benzenesulfonamide;-   N-(2-chlorophenyl)-3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;-   N-(2-chlorophenyl)-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;-   N-(2,3-difluorophenyl)-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;-   N-(2,5-difluorophenyl)-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;-   N-(2,6-difluorophenyl)-3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;-   N-(2,3-difluorophenyl)-3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;-   N-(2,5-difluorophenyl)-3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;-   N-(2,4-difluorophenyl)-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2    (1H)-ylcarbonyl]benzenesulfonamide;-   N-(2-fluorophenyl)-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2    (1H)-ylcarbonyl]benzenesulfonamide;-   N-(2,4-difluorophenyl)-3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;-   3-[(8    aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]-N-[2-(trifluoromethyl)phenyl]benzenesulfonamide;-   4-chloro-2-fluoro-N-(2-fluorophenyl)-5-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2    (1H)-ylcarbonyl]benzenesulfonamide;-   N-(3-chlorophenyl)-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;-   (8aR)-2-[3-({4-[bis(4-fluorophenyl)methyl]piperazin-1-yl}sulfonyl)benzoyl]octahydropyrrolo[1,2-a]pyrazine;-   (8aS)-2-[3-({4-[bis(4-fluorophenyl)methyl]piperazin-1-yl}sulfonyl)benzoyl]octahydropyrrolo[1,2-a]pyrazine;-   (8aR)-2-{3-[(4-benzhydrylpiperazin-1-yl)sulfonyl]benzoyl}octahydropyrrolo[1,2-a]pyrazine;-   N-(3-chlorophenyl)-3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;-   N-(2,2-diphenylethyl)-3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;-   3-[(8 aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]-N-[2-(tri    fluoromethyl)phenyl]benzenesulfonamide;-   (8aS)-2-{3-[(4-benzhydrylpiperazin-1-yl)sulfonyl]benzoyl}octahydropyrrolo[1,2-a]pyrazine;-   N-(3,3-diphenylpropyl)-3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;-   N-(3,3-diphenylpropyl)-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;-   N-(2,2-diphenylethyl)-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;-   4-chloro-3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]-N-[4-(trifluoromethyl)phenyl]benzenesulfonamide;-   N-[2-(4-fluorophenyl)ethyl]-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;-   2-chloro-5-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]-N-[4-(trifluoromethyl)phenyl]benzenesulfonamide;-   (8aS)-2-(3-{[4-(4-fluorophenyl)piperazin-1-yl]sulfonyl}benzoyl)octahydropyrrolo[1,2-a]pyrazine;-   N-1,1′-biphenyl-2-yl-3-[(8    aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl    carbonyl]benzenesulfonamide;-   3-(octahydro-2H-pyrido[1,2-a]pyrazin-2-ylcarbonyl)-N-[4-(trifluoromethyl)phenyl]benzenesulfonamide;-   3-(octahydro-2H-pyrido[1,2-a]pyrazin-2-ylcarbonyl)-N-[3-(trifluoromethyl)phenyl]benzenesulfonamide;-   N-(2-fluorophenyl)-3-(octahydro-2H-pyrido[1,2-a]pyrazin-2-ylcarbonyl)benzenesulfonamide;-   N-(4-fluorophenyl)-3-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]benzenesulfonamide;-   N-phenyl-3-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]benzenesulfonamide;-   3-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]-N-[4-(trifluoromethyl)phenyl]benzenesulfonamide;-   3-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]-N-[3-(trifluoromethyl)phenyl]benzenesulfonamide;-   N-(3-fluorophenyl)-3-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]benzenesulfonamide;-   N-(2-fluorophenyl)-3-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]benzenesulfonamide;-   3-(1,4′-bipiperidin-1′-ylcarbonyl)-N-(4-fluorophenyl)benzenesulfonamide;-   3-(1,4′-bipiperidin-1′-ylcarbonyl)-N-(2-fluorophenyl)benzenesulfonamide;-   3-(1,4′-bipiperidin-1′-ylcarbonyl)-N-(3-fluorophenyl)benzenesulfonamide;-   3-(1,4′-bipiperidin-1′-ylcarbonyl)-N-[4-(trifluoromethyl)phenyl]benzenesulfonamide;-   (8aR)-2-{[3-({4-[bis(4-fluorophenyl)methyl]piperazin-1-yl}carbonyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (8aS)-2-{[3-({4-[bis(4-fluorophenyl)methyl]piperazin-1-yl}carbonyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (8aR)-2-({3-[(4-benzhydrylpiperazin-1-yl)carbonyl]phenyl}sulfonyl)octahydropyrrolo[1,2-a]pyrazine;-   N-(2,2-diphenyl    ethyl)-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylsulfonyl]benzamide;-   (8aS)-2-({3-[(4-benzhydrylpiperazin-1-yl)carbonyl]phenyl}sulfonyl)octahydropyrrolo[1,2-a]pyrazine;-   N-(3,3-diphenylpropyl)-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylsulfonyl]benzamide;-   N-[2-(4-fluorophenyl)ethyl]-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylsulfonyl]benzamide;-   3-[(8    aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]-N-[(1S)-2-hydroxy-1-phenylethyl]benzenesulfonamide;-   4-chloro-2-fluoro-N-(2-fluorophenyl)-5-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;-   4-chloro-N-(3,3-diphenylpropyl)-2-fluoro-5-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;-   3-[(8    aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1R)-ylsulfonyl]-N-[(1R,2S)-2-phenylcyclopropyl]benzamide;-   3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]-N-[(1R,2S)-2-phenylcyclopropyl]benzenesulfonamide;-   4-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]-N-[(1S)-2-hydroxy-1-phenylethyl]benzenesulfonamide;-   (8aR)-2-[2-chloro-5-(2,3-dihydro-1H-indol-1-ylsulfonyl)-4-fluorobenzoyl]octahydropyrrolo[1,2-a]pyrazine;-   2,4-dichloro-N-(2-fluorophenyl)-5-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;-   N-{2-fluoro-5-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2    (1H)-ylcarbonyl]phenyl}-3-(tri fluoromethyl)benzenesulfonamide;-   4-chloro-2-fluoro-N-(2-fluorophenyl)-5-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]-N-methylbenzenesulfonamide;-   (8aR)-2-(2-chloro-4-fluoro-5-{[4-(4-fluorophenyl)piperazin-1-yl]sulfonyl}benzoyl)octahydropyrrolo[1,2-a]pyrazine;-   N-{2-chloro-5-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]phenyl}-4-fluorobenzamide;-   N-{3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]phenyl}-N-methyl-3-(trifluoromethyl)benzenesulfonamide;-   4-chloro-N-(2,2-diphenylethyl)-2-fluoro-5-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;-   N-{2-chloro-4-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]phenyl}-4-fluorobenzamide;-   N-{4-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]-2-methylphenyl}-2-naphthamide;-   3,5-dichloro-N-{2-fluoro-5-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]phenyl}benzamide;-   N-benzhydryl-4-chloro-2-fluoro-5-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;-   N-{2-chloro-4-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]phenyl}-2,2-diphenylacetamide;-   N-{2-chloro-4-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]phenyl}-2-naphthamide;-   N-{3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]phenyl}-N-isopropyl-3-(trifluoromethyl)benzenesulfonamide;-   N-{2-chloro-5-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]phenyl}-2,2-diphenylacetamide;-   N-benzhydryl-N-{2-chloro-5-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]phenyl}amine;-   N-benzhydryl-N-{3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]phenyl}amine;-   3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylsulfonyl]-N-[(1S)-2-hydroxy-1-phenylethyl]benzamide;-   N-benzhydryl-2-chloro-4-fluoro-5-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylsulfonyl]benzamide;    or-   2-chloro-N-cyclopropyl-4-fluoro-5-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylsulfonyl]benzamide.

Compounds of the present application may exist as stereoisomers wherein,asymmetric or chiral centers are present. These stereoisomers are “R” or“S” depending on the configuration of substituents around the chiralcarbon atom. The terms “R” and “S” used herein are configurations asdefined in IUPAC 1974 Recommendations for Section E, FundamentalStereochemistry, Pure Appl. Chem., 1976, 45: 13-30.

The present application contemplates various stereoisomers and mixturesthereof and these are specifically included within the scope of thisapplication. Stereoisomers include enantiomers and diastereomers, andmixtures of enantiomers or diastereomers. Individual stereoisomers ofcompounds of the present application may be prepared synthetically fromcommercially available starting materials which contain asymmetric orchiral centers or by preparation of racemic mixtures followed byresolution which is well known to those of ordinary skill in the art.These methods of resolution are exemplified by (1) attachment of amixture of enantiomers to a chiral auxiliary, separation of theresulting mixture of diastereomers by recrystallization orchromatography and liberation of the optically pure product from theauxiliary or (2) direct separation of the mixture of optical enantiomerson chiral chromatographic columns.

Geometric isomers may exist in the present compounds. The inventioncontemplates the various geometric isomers and mixtures thereofresulting from the disposition of substituents around a carbon-carbondouble bond, a carbon-nitrogen double bond, a cycloalkyl group, or aheterocycle group. Substituents around a carbon-carbon double bond or acarbon-nitrogen bond are designated as being of Z or E configuration andsubstituents around a cycloalkyl or a heterocycle are designated asbeing of cis or trans configuration.

Within the present invention it is to be understood that compoundsdisclosed herein may exhibit the phenomenon of tautomerism.

Thus, the formulae drawings within this specification can represent onlyone of the possible tautomeric or stereoisomeric forms. It is to beunderstood that the invention encompasses any tautomeric orstereoisomeric form, and mixtures thereof, and is not to be limitedmerely to any one tautomeric or stereoisomeric form utilized within thenaming of the compounds or formulae drawings.

The present invention also includes isotopically-labeled compounds,which are identical to those recited in formula (I), formula (II),formula (III) or formula (IV), but for the fact that one or more atomsare replaced by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number usually found in nature. Examples ofisotopes suitable for inclusion in the compounds of the invention arehydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine,such as, but not limited to ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P,³⁵S, ¹⁸F, and ³⁶Cl, respectively. Substitution with heavier isotopessuch as deuterium, i.e., ²H, can afford certain therapeutic advantagesresulting from greater metabolic stability, for example increased invivo half-life or reduced dosage requirements and, hence, may bepreferred in some circumstances. Compounds incorporatingpositron-emitting isotopes are useful in medical imaging andpositron-emitting tomography (PET) studies for determining thedistribution of receptors. Suitable positron-emitting isotopes that canbe incorporated in compounds of formula (I), formula (II), formula (III)or formula (IV) are ¹¹C, ¹³N, ¹⁵O, and ¹⁸F. Isotopically-labeledcompounds of formula (I), formula (II), formula (III) or formula (IV)can generally be prepared by conventional techniques known to thoseskilled in the art or by processes analogous to those described in theaccompanying Schemes and Examples using appropriate isotopically-labeledreagent in place of non-isotopically-labeled reagent.

c. BIOLOGICAL DATA

Abbreviations which have been used in the descriptions of BiologicalData that follow are: EGTA for ethylene glycol tetraacetic acid; FLIPRfor fluorometric imaging plate reader; HEPES for4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid; i.p. forintraperitoneal; Mg₂ATP for dimagnesium adenosine triphosphate complex;p.o. for per orem (by mouth); and TEA-Cl for tetraethylammoniumchloride.

(i) In Vitro Methods—Electrophysiologic Assessment of Calcium ChannelActivity:

Patch-clamp recordings were performed using HEK293 cells stablyexpressing hCa_(v)3.2. Cells were plated in T175 flasks and grown at 37°C. and under 5% CO₂ to approximately 50% confluency. On the day of theexperiment, cells were harvested with Detachin™ cell detachment solution(Genlantis, San Diego, Calif.) and maintained in serum-free culturemedium supplemented with 25 mM HEPES up to several hours prior toexperiment. Whole-cell patch-clamp recordings were obtained usingextracellular saline consisting of (mM): 87.5 CsCl, 40 TEA-Cl, 5 CaCl₂,1 MgCl₂, 10 HEPES, 10 glucose. The pH was adjusted to 7.2 with CsOH andthe osmolarity was adjusted to approximately 310 mOsm with sucrose.Intracellular solution consisted of (mM): 112 CsCl, 27 CsF, 2 NaCl, 8.2EGTA, 10 HEPES. Prior to an experiment 4 mM Mg₂ATP was added and the pHwas adjusted to 7.2 with CsOH with an osmolarity of approximately 290mOsm. A two-pulse voltage protocol was utilized to assess compoundinhibition. First, cells were held with an 8 s pre-pulse at −100 mVprior to a 160 ms test pulse to −30 mV. This was followed by an 8 spre-pulse at approximately −75 mV prior to a −160 mV test pulse to 30mV. Increasing concentrations of antagonist were applied to individualcells in a multi-addition format with 5 minutes in each testconcentration. For each cell, responses were normalized to dimethylsulfoxide vehicle control to generate concentration-response curves.

Table 1 lists IC₅₀ values for compounds of the present invention.

TABLE 1 Electrophysiologic Assessment for Human Cav3.2 Channels HumanCa_(v)3.2 −77 mV IC₅₀ (μM) Example Qualifier GeoMean 1 > 10 2 10.6 3 5.94 7.7 5 1.8 6 1.9 7 6.5 8 2.1 9 7.3 10 1.5 11 6.6 12 4.7 13 5.6 14 3.715 > 10 16 6.0 17 > 10 18 9.3 19 2.4 20 6 21 5.9 22 1.4 23 2.5 24 1.0 258.9 26 1.5 27 > 10 28 1.9 29 2.1 30 1.8 31 3.3 32 8.4 33 5.7 34 6.2 354.8 36 4.7 37 1.1 38 4.6 39 4.1 40 4.1 41 5.0 42 5.8 43 4.9 44 4.9 45 >10 46 1.8 47 3.8 48 > 10 49 1.3 50 0.6 51 0.9 52 0.6 53 0.5 54 1.2 551.8 56 4.1 57 48 58 4.6 59 9.0 60 5.0 61 > 10 62 > 10 63 > 10 64 1.7 651.84 66 5.9 67 3.18 68 10.9 69 > 10 70 7.2 71 10 72 > 10 73 1.8 74 2 756.5 76 6.4 77 > 10 78 > 10 79 8.5 80 2 81 > 10 82 2.6 83 > 10

(ii) In Vivo Data—Capsaicin Induced Secondary Mechanical HyperalgesiaModel:

Sprague Dawley rats were briefly restrained, and capsaicin wasadministered at 10 μg in 10 μL of vehicle by intraplantar injection intothe center of the right hind paw. Secondary mechanical hyperalgesia(SMH) was measured at the heel away from the site of injection 180minutes following capsaicin exposure. Compounds and gabapentin (positivecontrol), were administered p.o. 60 minutes before testing (2 hoursafter capsaicin) or i.p. 30 minutes before testing (2.5 hours aftercapsaicin). SMH was measured using calibrated von Frey filaments(Stoelting, Woodale, Ill.). Following the 1 hour habituation in thetesting room, rats were moved to individual plexiglass chambers that siton top of a wire mesh to allow for access for stimulation of the plantarsurface of the hind paws. Rats were allowed to acclimate to the newchambers for 15 minutes before the onset of testing. The paw withdrawalthreshold was determined by increasing and decreasing stimulus intensity(force: g) and calculated using Dixon's up-down method (Chaplan, S. R.;Bach, F. W.; Pogrel, J. W.; Chung, J. M.; Yaksh, T. L.; Quantitativeassessment of tactile allodynia in the rat paw. J. Neuroscience Methods1994, 53(1), 55-63.). The filaments (maximum force of 15.0 g) were heldin place for 8 seconds or until there was a withdrawal response from themechanical stimulation.

Table 2 lists results for representative examples of the presentinvention.

TABLE 2 Inhibition to Pain Response % inhibition @ Example 30 mg/kg p.o.2 58 3 44 13 37 20 43 37 63 64 57

d. METHODS OF USING THE COMPOUNDS

One embodiment of the present invention provides a method of treatingpain in a subject in need thereof. The method comprises administering tothe subject, including a mammal, such as a human, a therapeuticallysuitable amount of a compound of formula (I), formula (II), formula(III), or formula (IV), or a pharmaceutically acceptable salt thereof.Conditions related to pain include acute pain, chronic pain, neuropathicpain, inflammatory pain, visceral pain, cancer pain, allodynia,fibromyalgia, sciatica, back pain, and headache pain including migraine,or combinations thereof. Preferably, the method comprises administeringto the mammal a therapeutically effective amount of any of the compoundsas described herein, or a pharmaceutically acceptable salt thereof. Incertain embodiments, the method comprises administering to the mammal atherapeutically effective amount of any of the compounds as describedherein, or a pharmaceutically acceptable salt thereof, in combinationwith one or more of the following: nonsteroidal anti-inflammatory drug(NSAID), opioid analgesic, barbiturate, benzodiazapine, histamineantagonist, sedative, skeletal muscle relaxant, transient receptorpotential ion channel antagonist, α-adrenergic, tricyclicantidepressant, anti convulsant, tachykinin antagonist, muscarinicantagonist, cyclooxygenase-2 selective inhibitor, neuroleptic, vanilloidreceptor agonist, vanilloid receptor antagonist, β-adrenergic, localanesthetic, corticosteroid, 5-HT receptor agonist, 5-HT receptorantagonist, 5-HT_(2A) receptor antagonist, cholinergic analgesic, α₂δligand such as gabapentin or pregabalin, cannabinoid receptor ligand,metabotropic glutamate subtype 1 receptor antagonist, serotonin reuptakeinhibitor, norepinephrine reuptake inhibitor, dualserotonin-noradrenaline reuptake inhibitor, Rho kinase inhibitor,inducible nitric oxide synthase inhibitor, acetylcholinesteraseinhibitor, prostaglandin E₂ subtype 4 antagonist, leukotriene B4antagonist, 5-lipoxygenase inhibitor, sodium channel blocker, 5-HT3antagonist, N-methyl-D-aspartic acid receptor antagonist, orphosphodiesterase V inhibitor.

Yet another embodiment of the present invention relates to a method forproviding a method for treating disorders of the central nervous systemincluding stroke, epilepsy, manic depression, bipolar disorders,depression, anxiety, schizophrenia, migraine, and psychoses; neuraldegenerative disorders including Alzheimer's disease, AIDS relateddementia, Parkinson's disease, neuropathy caused by head injury, anddementia caused by cerebrovascular disorders; disorders of the lowerurinary tract including overactive bladder, prostatis, prostadynia,interstitial cystitis, and benign prostatic hyperplasia; disorderscaused by psychogenic stress including bronchial asthma, unstableangina, and hypersensitive colon inflammation; cardiovascular disordersincluding hypertension, atherosclerosis, heart failure, and cardiacarrhythmias; drug addiction withdrawal symptoms, including ethanoladdiction withdrawal symptoms; skin disorders including pruritis andallergic dermatitis, inflammatory bowel disease; cancer; diabetes; andinfertility and sexual dysfunction in a mammal in need of suchtreatment. This method comprises administering to the mammal (includinghuman) a therapeutically effective amount of a compound of the inventionor a pharmaceutically acceptable salt thereof.

Calcium channel blockers have been associated with a slightly greaterdecreased risk of stroke compared to other types of antihypertensiveagents (Angeli, F.; et al. Calcium channel blockade to prevent stroke inhypertension. American Journal of Hypertension 2004, 17(9), 817-822).The enhanced effect did not correlate with differences in systolic bloodpressure and the mechanism of action remains unknown. However, calciumchannel blockers have been associated with blockade of central neuronalcalcium influx and subsequent ischemic injury in two rodent models(Barone, F. C.; et al. SB 201823-A antagonizes calcium currents incentral neurons and reduces the effects of focal ischemia in rats andmice. Stroke 1995, 26, 1683-1690.). In another model of global ischemia,a calcium channel blocker offered neuroprotection although notpermanently (Colbourne, F.; et al. Continuing postischemic neuronaldeath in CA1: Influence of ischemia duration and cytoprotective doses ofNBQX and SNX-111 in rats. Stroke 1999, 30(3), 662-668.). Additionally,diminished progression of carotid atherosclerosis has been observed withcalcium channel blocker use (Zanchetti, A.; et al. Calcium antagonistlacidipine slows down progression of asymptomatic carotidatherosclerosis. Principal results of the European lacidipine study onatherosclerosis (ELSA), a randomized, double-blind, long-term trial.Circulation 2002, 106, r47-r52.).

An increase in intracellular calcium concentration has been correlatedwith seizure activity (Heinemann, U.; et al. Extracellular free calciumand potassium during paroxysmal activity in the cerebral cortex of thecat. Exp. Brain Res. 1977, 27, 237-243.). Several studies have indicatedthat calcium channel blockers produce anti convulsant activity (Vezzani,A.; et al. Effects of various calcium channel blockers on threedifferent models of limbic seizures in rats. Neuropharmacology 1988,27(5), 451-458. Otoom, S.; et al. Nifedipine inhibits picrotoxin-inducedseizure activity: further evidence on the involvement of L-type calciumchannel blockers in epilepsy. Fundamental & Clinical Pharmacology 2006,20, 115-119.).

Calcium channel blockers have been evaluated in the treatment of bipolardisorders and manic depression for decades. There are suggestions thatthe calcium channel subtype has influence on efficacy of these disorders(Gitlin, M. Treatment-resistant bipolar disorder. Molecular Psychiatry2006, 11, 227-240. Levy, N. A.; Janicak, P. G. Bipolar Disorders 2000,2, 108-119.).

Calcium channel blockers have also been associated with the treatment ofanxiety and depression (Saade, S.; et al. The L-type calcium channelblocker nimodipine mitigates “learned helplessness” in rats.Pharmacology, Biochemistry and Behavior 2003, 74, 269-278.).

Antischizophrenic drugs have been found to be calcium channelantagonists (Gould, R. J.; et al. Antischizophrenic drugs of thediphenylbutylpiperidine type act as calcium channel antagonists. Proc.Natl. Acad. Sci. USA 1983, 80, 5122-5125.). Other calcium channelblockers have been suggested for the treatment of schizophrenia (Tort,A. B. L.; et al. Atypical antipsychotic profile of flunarizine in animalmodels. Psychopharmacology 2005, 177, 344-348.).

Migraines are treated with calcium channel blockers (Arulmoshi, D. K.;et al. Migraine: Current concepts and emerging therapies. VascularPharmacology 2005, 43, 176-187. Gladstone, J. P.; et al. Current andemerging treatment options for migraine and other primary headachedisorders. Expert Rev. Neurotherapeutics 2003, 3(6), 845-872.).

Disorders of the lower urinary tract including overactive bladder,prostatis, prostadynia, interstitial cystitis, and benign prostatichyperplasia can be treated with calcium channel blockers (Fraser, M. O.;et al. US20050148587, 2005).

Ethanol withdrawal syndrome is decreased with calcium channel blockers(Little, H. J.; et al. Calcium channel antagonists decrease the ethanolwithdrawal syndrome. Life Sciences 1986, 39, 2059-2065.).

Several cardiac disorders are treated with calcium channel blockers.Atherosclerosis may be reduced by a decrease in free radical-mediateddamage as a result of influence on the biophysical properties ofmembranes (Mason, R. P.; et al. Antioxidant and cytoprotectiveactivities of the calcium channel blocker mibefradil. BiochemicalPharmacology 1998, 55, 1843-1852.). Hypertension and angina are bothsuccessfully treated with calcium channel blockers (Croom, K. F.; et al.Modified-release nifedipine: A review of the use of modified-releaseformulations in the treatment of hypertension and angina pectoris. Drugs2006, 66(4), 497-528.).

There is data suggesting that calcium channel blockers inhibit theproliferation of cancer cells (Gray, L. S.; et al. InternationalPublication No. WO200059882, 2000.).

Calcium channels have been suggested as a target for the treatment ofdiabetes (Bhattacharjee, A.; et al. T-Type calcium channels facilitateinsulin secretion by enhancing general excitability in theinsulin-secreting β-cell line, INS-1. Endocrinology 1997, 138(9),3735-3740.).

Ion channels including calcium channels play an important role in spermphysiology and fertilization (Darszon, A.; et al. Ion channels in spermphysiology. Physiological Reviews 1999, 79(2), 481-510).

Calcium channel blockers modulate inflammation (Bilici, D.; et al.Protective effect of T-type calcium channel blocker in histamine-inducedpaw inflammation in rat. Pharmacological Research 2001, 44(6),527-531.).

Increased calcium levels in neurones has been implicated in Alzheimer'sdisease. Two suggested mechanisms of increased calcium influx are thatβ-amyloid may form calcium permeable channels (Bhatia, R.; et al. Freshand globular amyloid beta protein (1-42) induces rapid cellulardegeneration: evidence for APP channel-mediated cellular toxicity. FASEBJ. 2000, 14(9), 1233-1243.) or a G-protein-coupled receptor may beactivated by β-amyloid (Lorton, D. β-Amyloid induced IL-1 β release froman activated human monocyte cell line is calcium- andG-protein-dependent. Mech. Ageing Dev. 1997, 94(1-3), 199-211.).Neurodegenerative diseases, including Parkinson's and Alzheimer'sdiseases can be modulated by calcium channel blockers (Rodnitzky, R. L.Can calcium antagonists provide a neuroprotective effect in Parkinson'sdisease. Drugs 1999, 57(6), 845-849. Vagnucci, A. H., Jr.; et al.Alzheimer's disease and angiogenesis. The Lancet 2003, 361(9357),605-608. Veng, L. M.; et al. Age-related working memory impairment iscorrelated with increases in the L-type calcium channel protein α_(1D)(Ca_(v)1.3) in area CA1 of the hippocampus and both are ameliorated bychronic nimodipinc treatment. Molecular Brain Research 2203, 110,193-202. Geldenhuys, W. J.; et al. Structure-activity relationships ofpentacycloundecylamines at the N-methyl-D-aspartate receptor. Bioorganicand Medicinal Chemistry 2007, 15, 1525-1532. Cavalli, A.; et al.Multi-target-directed ligands to combat neurodegenerative diseases. J.Med. Chem. 2008, 51(3), 347-372.)

Actual dosage levels of active ingredients in the pharmaceuticalcompositions of this invention can be varied so as to obtain an amountof the active compound(s) that is effective to achieve the desiredtherapeutic response for a particular patient, compositions and mode ofadministration. The selected dosage level depends upon the activity ofthe particular compound, the route of administration, the severity ofthe condition being treated and the condition and prior medical historyof the patient being treated. However, it is within the skill of the artto start doses of the compound at levels lower than required to achievethe desired therapeutic effect and to gradually increase the dosageuntil the desired effect is achieved.

Compounds of the invention can also be administered as a pharmaceuticalcomposition comprising the compounds of interest in combination with oneor more pharmaceutically acceptable carriers. The phrase“therapeutically effective amount” of the compound of the inventionmeans a sufficient amount of the compound to treat disorders, at areasonable benefit/risk ratio applicable to any medical treatment. It isunderstood, however, that the total daily usage of the compounds andcompositions of the invention will be decided by the attending physicianwithin the scope of sound medical judgment. The specific therapeuticallyeffective dose level for any particular patient depends upon a varietyof factors including the disorder being treated and the severity of thedisorder; activity of the specific compound employed; the specificcomposition employed; the age, body weight, general health, sex and dietof the patient; the time of administration, route of administration, andrate of excretion of the specific compound employed; the duration of thetreatment; drugs used in combination or coincidental with the specificcompound employed; and like factors well-known in the medical arts. Forexample, it is well within the skill of the art to start doses of thecompound at levels lower than required to achieve the desiredtherapeutic effect and to gradually increase the dosage until thedesired effect is achieved.

The total daily dose of the compounds of this invention administered toa human or other animal range from about 0.01 mg/kg body weight to about100 mg/kg body weight. More preferable doses can be in the range of fromabout 0.01 mg/kg body weight to about 30 mg/kg body weight. If desired,the effective daily dose can be divided into multiple doses for purposesof administration. Consequently, single dose compositions may containsuch amounts or submultiples thereof to make up the daily dose.

e. PHARMACEUTICAL COMPOSITIONS

The present invention further provides pharmaceutical compositions thatcomprise compounds of the present invention or a pharmaceuticallyacceptable salt or solvate thereof. The pharmaceutical compositionscomprise compounds of the present invention that may be formulatedtogether with one or more non-toxic pharmaceutically acceptablecarriers.

Another aspect of the present invention is a pharmaceutical compositioncomprising compounds of the invention, or a pharmaceutically acceptablesalt thereof, and one or more pharmaceutically acceptable carriers,alone or in combination with one or more nonsteroidal anti-inflammatorydrugs (NSAID), opioid analgesics, barbiturates, benzodiazepines,histamine antagonists, sedatives, skeletal muscle relaxants, transientreceptor potential ion channel antagonists, α-adrenergics, tricyclicantidepressants, anticonvulsants, tachykinin antagonists, muscarinicantagonists, cyclooxygenase-2 selective inhibitors, neuroleptics,vanilloid receptor agonists, vanilloid receptor antagonists,β-adrenergics, local anesthetics, corticosteroids, 5-HT receptoragonists, 5-HT receptor antagonists, 5-HT_(2A) receptor antagonists,cholinergic analgesics, α₂δ ligands such as gabapentin or pregabalin,cannabinoid receptor ligands, metabotropic glutamate subtype 1 receptorantagonists, serotonin reuptake inhibitors, norepinephrine reuptakeinhibitors, dual serotonin-noradrenaline reuptake inhibitors, Rho kinaseinhibitors, inducible nitric oxide synthase inhibitors,acetylcholinesterase inhibitors, prostaglandin E₂ subtype 4 antagonists,leukotriene B4 antagonists, 5-lipoxygenase inhibitors, sodium channelblockers, 5-HT3 antagonists, N-methyl-D-aspartic acid receptorantagonists, and phosphodiesterase V inhibitors.

The pharmaceutical compositions of this invention can be administered tohumans and other mammals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments or drops), bucally or as an oral or nasal spray. Theterm “parenterally” as used herein, refers to modes of administrationwhich include intravenous, intramuscular, intraperitoneal, intrasternal,subcutaneous and intraarticular injection and infusion.

The term “pharmaceutically acceptable carrier” as used herein, means anon-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Someexamples of materials which can serve as pharmaceutically acceptablecarriers are sugars such as, but not limited to, lactose, glucose andsucrose; starches such as, but not limited to, corn starch and potatostarch; cellulose and its derivatives such as, but not limited to,sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients such as, but notlimited to, cocoa butter and suppository waxes; oils such as, but notlimited to, peanut oil, cottonseed oil, safflower oil, sesame oil, oliveoil, corn oil and soybean oil; glycols; such a propylene glycol; esterssuch as, but not limited to, ethyl oleate and ethyl laurate; agar;buffering agents such as, but not limited to, magnesium hydroxide andaluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;Ringer's solution; ethyl alcohol, and phosphate buffer solutions, aswell as other non-toxic compatible lubricants such as, but not limitedto, sodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants can also be present inthe composition, according to the judgment of the formulator.

Pharmaceutical compositions of this invention for parenteral injectioncomprise pharmaceutically acceptable sterile aqueous or nonaqueoussolutions, dispersions, suspensions or emulsions as well as sterilepowders for reconstitution into sterile injectable solutions ordispersions just prior to use. Examples of suitable aqueous andnonaqueous carriers, diluents, solvents or vehicles include water,ethanol, polyols (such as glycerol, propylene glycol, polyethyleneglycol and the like), vegetable oils (such as olive oil), injectableorganic esters (such as ethyl oleate) and suitable mixtures thereof.Proper fluidity can be maintained, for example, by the use of coatingmaterials such as lecithin, by the maintenance of the required particlesize in the case of dispersions and by the use of surfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms can be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid and the like. It may also be desirableto include isotonic agents such as sugars, sodium chloride and the like.Prolonged absorption of the injectable pharmaceutical form can bebrought about by the inclusion of agents which delay absorption such asaluminum monostearate and gelatin.

In some cases, in order to prolong the effect of the drug, it isdesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This can be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered drug form is accomplished by dissolving or suspending thedrug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules. In such solid dosage forms, the activecompound may be mixed with at least one inert, pharmaceuticallyacceptable excipient or carrier, such as sodium citrate or dicalciumphosphate and/or a) fillers or extenders such as starches, lactose,sucrose, glucose, mannitol and silicic acid; b) binders such ascarboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as cetyl alcoholand glycerol monostearate; h) absorbents such as kaolin and bentoniteclay and i) lubricants such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate and mixturesthereof. In the case of capsules, tablets and pills, the dosage form mayalso comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such carriers as lactose ormilk sugar as well as high molecular weight polyethylene glycols and thelike.

The solid dosage forms of tablets, dragees, capsules, pills and granulescan be prepared with coatings and shells such as enteric coatings andother coatings well-known in the pharmaceutical formulating art. Theymay optionally contain opacifying agents and may also be of acomposition such that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

The active compounds can also be in micro-encapsulated form, ifappropriate, with one or more of the above-mentioned carriers.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art such as, for example, water orother solvents, solubilizing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethyl formamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan andmixtures thereof.

Besides inert diluents, the oral compositions may also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar, tragacanth and mixtures thereof.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating carriers or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat room temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active compound.

Compounds of the present invention can also be administered in the formof liposomes. As is known in the art, liposomes are generally derivedfrom phospholipids or other lipid substances. Liposomes are formed bymono- or multi-lamellar hydrated liquid crystals which are dispersed inan aqueous medium. Any non-toxic, physiologically acceptable andmetabolizable lipid capable of forming liposomes can be used. Thepresent compositions in liposome form can contain, in addition to acompound of the present invention, stabilizers, preservatives,excipients and the like. The preferred lipids are natural and syntheticphospholipids and phosphatidyl cholines (lecithins) used separately ortogether.

Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y. (1976), p. 33 et seq.

Dosage forms for topical administration of a compound of this inventioninclude powders, sprays, ointments and inhalants. The active compoundmay be mixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives, buffers or propellants which maybe required. Ophthalmic formulations, eye ointments, powders andsolutions are also contemplated as being within the scope of thisinvention.

The compounds of the present invention can be used in the form ofpharmaceutically acceptable salts derived from inorganic or organicacids. The phrase “pharmaceutically acceptable salt” means those saltswhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response and the like and arecommensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge et al. describe pharmaceutically acceptable saltsin detail in (J. Pharmaceutical Sciences, 1977, 66: 1 et seq). The saltscan be prepared in situ during the final isolation and purification ofthe compounds of the invention or separately by reacting a free basefunction with a suitable organic acid. Representative acid additionsalts include, but are not limited to acetate, adipate, alginate,citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,camphorate, camphorsulfonate, digluconate, glycerophosphate,hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isothionate),lactate, malate, maleate, methanesulfonate, nicotinate,2-naphthalenesulfonate, oxalate, palmitoate, pectinate, persulfate,3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate,thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate andundecanoate. Also, the basic nitrogen-containing groups can bequaternized with such agents as lower alkyl halides such as, but notlimited to, methyl, ethyl, propyl, and butyl chlorides, bromides andiodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamylsulfates; long chain halides such as, but not limited to, decyl, lauryl,myristyl and stearyl chlorides, bromides and iodides; arylalkyl halideslike benzyl and phenethyl bromides and others. Water or oil-soluble ordispersible products are thereby obtained. Examples of acids which canbe employed to form pharmaceutically acceptable acid addition saltsinclude such inorganic acids as hydrochloric acid, hydrobromic acid,sulfuric acid, and phosphoric acid and such organic acids as aceticacid, fumaric acid, maleic acid, 4-methylbenzenesulfonic acid, succinicacid and citric acid.

Basic addition salts can be prepared in situ during the final isolationand purification of compounds of this invention by reacting a carboxylicacid-containing moiety with a suitable base such as, but not limited to,the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptablemetal cation or with ammonia or an organic primary, secondary ortertiary amine. Pharmaceutically acceptable salts include, but are notlimited to, cations based on alkali metals or alkaline earth metals suchas, but not limited to, lithium, sodium, potassium, calcium, magnesiumand aluminum salts and the like and nontoxic quaternary ammonia andamine cations including ammonium, tetramethylammonium,tetraethylammonium, methylammonium, dimethylammonium, trimethylammonium,tri ethyl ammonium, diethylammonium, ethyl ammonium and the like. Otherrepresentative organic amines useful for the formation of base additionsalts include ethylenediamine, ethanolamine, diethanolamine, piperidine,piperazine and the like.

The term “pharmaceutically acceptable prodrug” or “prodrug” as usedherein, represents those prodrugs of the compounds of the presentinvention which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio, and effective fortheir intended use.

The present invention contemplates compounds of the invention formed bysynthetic means or formed by in vivo biotransformation of a prodrug.

The compounds of the invention can exist in unsolvated as well assolvated forms, including hydrated forms, such as hemi-hydrates. Ingeneral, the solvated forms, with pharmaceutically acceptable solventssuch as water and ethanol among others are equivalent to the unsolvatedforms for the purposes of the invention.

f. GENERAL SYNTHESIS

This invention is intended to encompass compounds of the invention whenprepared by synthetic processes or by metabolic processes. Preparationof the compounds by metabolic processes includes those occurring in thehuman or animal body (in vivo) or processes occurring in vitro.

The compounds of the invention may be prepared by a variety of processeswell known for the preparation of compounds of this class. For example,the compounds of the invention wherein the groups L¹, R¹, R², R³, R⁴,R⁵, R⁶, R⁷, R^(c), X, and Y have the meanings as set forth in theSummary of the Invention section unless otherwise noted, can besynthesized as shown in Schemes 1-9.

Abbreviations which have been used in the descriptions of the Schemesand the Examples that follow are: DMSO for dimethyl sulfoxide; ESI forelectrospray ionization; and Et for ethyl.

Compounds of formula (I-2) wherein R³, R⁴, R⁵ and R⁶ are as defined forformula (I) can be prepared as described in Scheme 1. Compounds offormula (1-1) can be treated with excess oxalyl chloride optionally inthe presence of N,N-dimethylformamide in a solvent such asdichloromethane or toluene at a temperature from room temperature to thereflux temperature of the reaction solvent. Alternatively, a carboxylicacid of formula (1-1) can be reacted with thionyl chloride optionally inthe presence of N,N-dimethylformamide at a temperature from roomtemperature to refluxing to furnish compounds of formula (1-2).

Compounds of formula (2-2) wherein R³, R⁴, R⁵ and R⁶ are as defined forformula (I) can be prepared as described in Scheme 2. Accordingly,compounds of formula (1-2) which are obtained commercially or obtainedfrom the procedures described in Scheme 1 can be reacted with X—H,wherein the H is a hydrogen on a nitrogen atom contained within aheterocycle and X is said heterocycle as described in the Summary of theInvention, in the presence of a base such as sodium carbonate in asolvent such as dichloromethane at room temperature from 2-24 hours toprovide compounds of formula (2-1). Compounds of formula (2-1) can becarried on without isolation or purification by treatment with excessY—H, wherein the H is a hydrogen on a nitrogen atom contained within aheterocycle or primary amine, and wherein Y is as described in theSummary of the Invention, over 1 to 4 days at ambient temperature in asolvent such as dichloromethane or with heating in a neat mixture of theamine to give compounds of formula (2-2) which are representative ofcompounds of formula (I).

Compounds of formula (3-2) wherein R³, R⁴, R⁵ and R⁶ are as defined forformula (I) can be prepared as described in Scheme 3. Compounds offormula (1-2) which are obtained commercially or obtained from theprocedures described in Scheme 1 can be reacted with excess Y—H, whereinthe H is a hydrogen on a nitrogen atom contained within a heterocycle orprimary amine, and wherein Y is as described in the Summary of theInvention, in the presence of a base such as sodium carbonate in asolvent such as dichloromethane at room temperature from 2-24 hours toprovide compounds of formula (3-1). Compounds of formula (3-1) can becarried on without isolation or purification by treatment with X—H,wherein the H is a hydrogen on a nitrogen atom contained within aheterocycle, and wherein X is as described in the Summary of theInvention, optionally initially at reflux and then over 1 to 4 days atambient temperature to give compounds of formula (3-2) which arerepresentative of compounds of formula (I).

Compounds of formula (4-2) and formula (4-3) wherein R³, R⁴, R⁵ and R⁶are as defined for formula (II) can be prepared as described in Scheme4. Compounds of formula (4-1) which are obtained commercially orobtained from the corresponding benzoic acid according to the proceduresdescribed in Scheme 1 can be reacted in the sequences described inScheme 2 and Scheme 3 to give compounds of formula (4-2) and formula(4-3), respectively. Compounds of formula (4-2) and formula (4-3) arerepresentative of compounds of formula (II).

Compounds of formula (5-3) and (5-4) which are representative ofcompounds of formula (III), wherein R³, R⁴, R⁵, R⁶, R^(c), X and Y areas described in the Summary of the Invention, can be prepared asdescribed in Scheme 5. Reacting compounds of formula (5-1) with X—H,wherein the H is a hydrogen on a nitrogen atom contained within aheterocycle and X is said heterocycle as described in the Summary of theInvention, under amide bond coupling conditions gives compounds offormula (5-2). Examples of conditions known to generate amides from amixture of a carboxylic acid and an amine include but are not limited toadding a coupling reagent such as but not limited toN-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDC or EDCI),1,3-dicyclohexylcarbodiimide (DCC), bis(2-oxo-3-oxazolidinyl)phosphinicchloride (BOPCl),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU),O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (HBTU), and2-(3H[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V). The coupling reagents may be added as a solid, asolution or as the reagent bound to a solid support resin. In additionto the coupling reagents, auxiliary-coupling reagents may facilitate thecoupling reaction. Auxiliary coupling reagents that are often used inthe coupling reactions include but are not limited to(dimethylamino)pyridine (DMAP), 1-hydroxy-7-azabenzotriazole (HOAT) and1-hydroxybenzotriazole (HOBT). The reaction may be carried outoptionally in the presence of a base such as triethylamine ordiisopropylethylamine. The coupling reaction may be carried out insolvents such as but not limited to tetrahydrofuran,N,N-dimethylformamide, dichloromethane, and ethyl acetate or mixturesthereof. The reaction may be conducted at ambient or elevatedtemperatures. Compounds of formula (5-2) can then be reacted withsulfonyl chlorides of formula Y—SO₂Cl in the presence of a base such assodium carbonate or triethylamine in a solvent such asN,N-dimethylformamide either at ambient or elevated temperature tosupply compounds of formula (5-3). In similar fashion, compounds offormula (5-2) can be reacted with an acid chloride of formula Y—C(O)Clto give compounds of formula (5-4).

Compounds of formula (6-3) and (6-4) which are representative ofcompounds of formula (IV), wherein R³, R⁴, R⁵, R⁶, R^(c), X and Y are asdescribed in the Summary of the Invention, can be prepared as describedin Scheme 6. The methodology described in Scheme 5 can be used toconvert compounds of formula (6-1) into compounds of formula (6-2).Subsequently, compounds of formula (6-2) can be transformed to eithercompounds of formula (6-3) or (6-4) also using the procedures describedin Scheme 5.

Compounds of formula (5-3) which are representative of compounds offormula (III), wherein R³, R⁴, R⁵, R⁶, R^(c), X and Y are as describedin the Summary of the Invention, can be prepared as described in Scheme7. Compounds of formula (7-1), wherein LG¹ is a leaving group such asbromine, iodine, or trifluoromethansulfonate, may be reacted incross-coupling reactions with amines of formula H₂NR^(c) to supplycompounds of formula (7-2). The coupling reactions are typicallyconducted in the presence of a metal catalyst such as palladium orcopper with appropriate ligands, bases, temperature, and solventssuggested in the following references: For reviews of Pd catalyzedreaction, see: (a) Schlummcr, B.; Scholz, U. Adv. Synth. Catal. 2004,346, 1599. (b) Jiang, L.; Buchwald, S. L. in Metal CatalyzedCross-Coupling Reactions, 2nd ed.; de Meijere, A.; Diederich, F.; Eds.;John Wiley & Sons: Weinheim, 2004. For reviews of Cu catalyzedreactions, see (c) Ley, S. V.; Thomas, A. W. Angew. Chem. Int. Ed. 2003,42, 5400. Compounds of formula (7-2) can then be reacted with sulfonylchlorides of formula ClSO₂—Y in heated pyridine to give sulfonamides offormula (7-3). The ester moiety of compounds of formula (7-3) can thenbe hydrolyzed by conditions well known in the art, and then the exposedcarboxylic acid can then be coupled with a compound of formula X—H,wherein the H is a hydrogen on a nitrogen atom contained within aheterocycle and X is said heterocycle as described in the Summary of theInvention, under the amide bond coupling conditions described in Scheme5 to give compounds of formula (5-3).

Compounds of formula (6-3), which are representative of compounds offormula (IV), wherein R³, R⁴, R⁵, R⁶, R^(c), X and Y are as described inthe Summary of the Invention, can be prepared as described in Scheme 8.The methodology described in Scheme 7 can be used to convert compoundsof formula (8-1) into compounds of formula (6-3).

Compounds of formula (9-2) and formula (9-4), wherein R³, R⁴, R⁵, R⁶, Xand Y are as described in the Summary of the Invention, can be preparedas described in Scheme 9 from compounds of formula (9-1) and (9-3),respectively, which are representative of compounds of formula (III) andformula (IV), respectively. Accordingly, compounds of formula (9-1),which can be prepared with the methodology described in Scheme 5 for thepreparation of compounds of formula (5-2), can be reacted with compoundof formula Y-LG², wherein Y is either a benzyl or benzhydryl group andLG² is a chloro, bromo, iodo, or sulfonate, in the presence of a basesuch as sodium carbonate in a heated solvent such asN,N-dimethylformamide to give compounds of formula (9-2). The heatingmay either be conventional or carried out in a microwave reactor.Compounds of formula (9-3) can be reacted in like manner to givecompounds of formula (9-4).

Compounds of formula (2-2), wherein R³, R⁴, R⁵, R⁶, X and Y are asdescribed in the Summary of the Invention, can also be prepared asdescribed in Scheme 10 from compounds of formula (10-1). Alkyl3-(chlorosulfonyl)benzoate (10-1) can be reacted with excess Y—H,wherein the H is a hydrogen on a nitrogen atom contained within aheterocycle or primary amine, and wherein Y is as described in theSummary of the Invention, over 1 to 8 hours at ambient temperature in asolvent such as N,N-dimethylacetamide. Subsequent hydrolysis underconditions known to one skilled in the art supplies benzoic acid analogsof formula (10-2). Coupling of compounds of formula (10-2) withcompounds of formula X—H, wherein the H is a hydrogen on a nitrogen atomcontained within a heterocycle and X is said heterocycle as described inthe Summary of the Invention, under amide bond coupling conditions givescompounds of formula (2-2). Examples of conditions known to generateamides from a mixture of a carboxylic acid and an amine include but arenot limited to adding a coupling reagent such as but not limited toN-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDC or EDCI),1,3-dicyclohexylcarbodiimide (DCC), bis(2-oxo-3-oxazolidinyl)phosphinicchloride (BOPCl),0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU),O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (HBTU), and2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V). The coupling reagents may be added as a solid, asolution or as the reagent bound to a solid support resin. In additionto the coupling reagents, auxiliary-coupling reagents may facilitate thecoupling reaction. Auxiliary coupling reagents that are often used inthe coupling reactions include but are not limited to(dimethylamino)pyridine (DMAP), 1-hydroxy-7-azabenzotriazole (HOAT) and1-hydroxybenzotriazole (HOBT). The reaction may be carried outoptionally in the presence of a base such as triethylamine ordiisopropylethylamine. The coupling reaction may be carried out insolvents such as but not limited to tetrahydrofuran,2-methyltetrahydrofuran, N,N-dimethylformamide, dichloromethane, andethyl acetate or mixtures thereof. The reaction may be conducted atambient or elevated temperatures. Compounds of formula (2-2) arerepresentative of compounds of formula (I).

Compounds of formula (4-2), wherein R³, R⁴, R⁵ and R⁶ are as defined forformula (II) can also be prepared as described in Scheme 11. Compoundsof formula (11-1) can be reacted in the sequences described in Scheme 10to give compounds of formula (4-2). Compounds of formula (4-2) arerepresentative of compounds of formula (II).

It is appreciated that the synthetic schemes and specific examples asillustrated in the Examples section are illustrative and are not to beread as limiting the scope of the invention as it is defined in theappended claims. All alternatives, modifications, and equivalents of thesynthetic methods and specific examples are included within the scope ofthe claims.

Optimum reaction conditions and reaction times for each individual stepmay vary depending on the particular reactants employed and substituentspresent in the reactants used. Unless otherwise specified, solvents,temperatures and other reaction conditions may be readily selected byone of ordinary skill in the art. Specific procedures are provided inthe Examples section. Reactions may be worked up in the conventionalmanner, e.g. by eliminating the solvent from the residue and furtherpurified according to methodologies generally known in the art such as,but not limited to, crystallization, distillation, extraction,trituration and chromatography. Unless otherwise described, the startingmaterials and reagents are either commercially available or may beprepared by one skilled in the art from commercially available materialsusing methods described in the chemical literature.

Routine experimentations, including appropriate manipulation of thereaction conditions, reagents and sequence of the synthetic route,protection of any chemical functionality that may not be compatible withthe reaction conditions, and deprotection at a suitable point in thereaction sequence of the method are included in the scope of theinvention. Suitable protecting groups and the methods for protecting anddeprotecting different substituents using such suitable protectinggroups are well known to those skilled in the art; examples of which maybe found in T. Greene and P. Wuts, Protecting Groups in ChemicalSynthesis (3^(rd) ed.), John Wiley & Sons, NY (1999), which isincorporated herein by reference in its entirety. Synthesis of thecompounds of the invention may be accomplished by methods analogous tothose described in the synthetic schemes described hereinabove and inspecific examples.

Starting materials, if not commercially available, may be prepared byprocedures selected from standard organic chemical techniques,techniques that are analogous to the synthesis of known, structurallysimilar compounds, or techniques that are analogous to the abovedescribed schemes or the procedures described in the synthetic examplessection.

When an optically active form of a compound of the invention isrequired, it may be obtained by carrying out one of the proceduresdescribed herein using an optically active starting material (prepared,for example, by asymmetric induction of a suitable reaction step), or byresolution of a mixture of the stereoisomers of the compound orintermediates using a standard procedure (such as chromatographicseparation, recrystallization or enzymatic resolution).

Similarly, when a pure geometric isomer of a compound of the inventionis required, it may be obtained by carrying out one of the aboveprocedures using a pure geometric isomer as a starting material, or byresolution of a mixture of the geometric isomers of the compound orintermediates using a standard procedure such as chromatographicseparation.

g. EXAMPLES Example 13-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]-N-[4-(trifluoromethyl)phenyl]benzenesulfonamide

Step A:

To 3-(chlorosulfonyl)benzoyl chloride (0.359 g, 1.5 mmol) in anhydrousdichloromethane (80 mL) was added (R)-octahydropyrrolo[1,2-a]pyrazine(0.189 g, 1.5 mmol) in dichloromethane (4 mL) slowly over 10 minutes atroom temperature. Then sodium carbonate (0.32 g, 2 mmol) was added, andthe mixture was stirred at room temperature for 5 hours. Subsequently4-(trifluoromethyl)aniline (2.42 g, 15 mmol) was added. The mixture wasstirred at room temperature for 3 days, and then sodium carbonate (0.32g, 3 mmol) and methanol (5 mL) were added. The mixture was stirred for20 minutes, then filtered, and concentrated under reduced pressure. Theresidue was purified by chromatography on silica gel (methanol/ethylacetate=1:10) to give the titled compound: ¹H NMR (400 MHz, DMSO-d₆) δppm 1.10-1.90 (m, 6H), 2.10 (m, 1H), 2.70-3.15 (m, 5H), 4.40-4.60 (m,1H), 7.30 (d, 2H, J=7 Hz), 7.63 (m, 4H), 7.76 (br s, 1H), 7.90 (m, 1H),10.85 (br s, 1H); MS (ESI) m/z 454 (M+H)⁺.

Step B:

To the above compound (560 mg, 1.236 mmol) was added 2 mL of 1 N HClsolution and 1 mL of methanol, and then the mixture was concentrated todryness to give the HCl salt of the titled compound: ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.60-2.20 (m, 4H), 2.90-3.90 (m, 8H), 4.60-4.80 (m, 1H),7.35 (d, 2H, J=7 Hz), 7.62 (d, 2H, J=7 Hz), 7.72 (m, 2H), 7.92 (m, 2H),11.06 (m, 1H), 11.50 (m, 1H); MS (ESI) m/z 454 (M+H)⁺.

Example 2N-(2-fluorophenyl)-3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide

Step A:

To ethyl 3-(chlorosulfonyl)benzoate (1 g, 4.02 mmol) inN,N-dimethylacetamide (13.4 mL) was added 2-fluoroaniline (1.551 mL,16.08 mmol) dropwise over 1 minute at room temperature. The mixture wasstirred at room temperature for 1 hour and then diluted with ethylacetate (35 mL). The organic solution was washed with 1 N HCl (2×13 mL)and saturated NaCl (13 mL). The organic layer was concentrated, ethanol(38 mL) was added to the reside, and the mixture was concentrated togive ethyl 3-{[(2-fluorophenyl)amino]sulfonyl}benzoate.

Step B:

To the product of Step A was added ethanol (8 mL) followed by a solutionof NaOH (0.483 g, 12.06 mmol) in water (8 mL). The reaction was stirredat ambient temperature for 45 minutes. To the mixture was added 1 N HCl(23 mL) and the mixture was stirred overnight. The solids were collectedby filtration, washed with water (1×5 mL) and dried by vacuum filtrationto give 3-{[(2-fluorophenyl)amino]sulfonyl}benzoic acid: ¹H-NMR: (400MHz, DMSO-d₆) δ ppm 13.97 (bs, 1H), 10.62 (bs, 1H), 8.26 (dd, 1H, J=1.6,1.6, 3.2 Hz), 8.16 (ddd, 1H, J=8.1, 1.1, 1.1 Hz), 7.90 (ddd, 1H, J=8.1,1.4, 1.4 Hz), 7.68 (dd, 1H, J=7.8, 7.8 Hz), 7.25-7.1 (m, 4H); MS (ESI)m/z 294.2 (M−H)⁻.

Step C:

To a mixture of 3-{[(2-fluorophenyl)amino]sulfonyl}benzoic acid (800 mg,2.71 mmol) and2-(3H-[1,2,3]triazolo[4,5-h]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (1133 mg, 2.98 mmol) in N,N-dimethylacetamide(6.5 mL) and 2-methyltetrahydrofuran (19.5 mL) was added(R)-octahydropyrrolo[1,2-a]pyrazine (479 mg, 3.79 mmol). The reactionwas stirred at room temperature for 3 hours, diluted with2-methyltetrahydrofuran (5 mL), and washed with saturated bicarbonate(2×25 mL). The combined aqueous layers were adjusted to pH 7 with bufferand re-extracted with 2-methyltetrahydrofuran (3×15 mL). The combinedorganic layers were concentrated under reduced pressure. The residue wastaken up in ethanol (25 mL) and concentrated to give the title compound.

Step D:

To the product of Step C was added ethanol (25 mL) and then concentratedHCl (0.11 g, 2.98 mmol) in ethanol (1 mL) dropwise over 1 minute. Themixture was stirred at ambient temperature overnight and concentrated toafford the title compound as the hydrochloride salt: ¹H NMR (400 MHz,DMSO-d6) δ ppm 11.35-11.05 (m, 1H), 10.30 (bs, 1H), 8.30-7.63 (m, 4H),7.28-7.09 (m, 4H), 4.85-4.55 (m, 1H), 3.95-2.95 (m, 8H), 2.28-1.45 (m,4H); MS (ESI) m/z 404.2 (M+H)⁺.

Example 3N-(3-fluorophenyl)-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide

Step A:

To ethyl 3-(chlorosulfonyl)benzoate (1.0 g, 4.02 mmol) inN,N-dimethylacetamide (5 mL) was added 3-fluoroaniline (1.79 g, 16.08mmol) dropwise over 30 seconds at room temperature. The mixture wasstirred at room temperature for 4 hours, and then it was diluted withethyl acetate (33 mL). The organic solution was washed with 1 N HCl(2×13 mL) and saturated NaCl (13 mL). The organic layer wasconcentrated, ethanol (8 mL) was added, and the mixture concentrated togive ethyl 3-{[(3-fluorophenyl)amino]sulfonyl}benzoate.

Step B:

To the product of Step A was added ethanol (6.4 mL) followed by asolution of NaOH (0.483 g, 12.1 mmol) in water (6.4 mL). The reactionwas stirred at ambient temperature for 1 hour. To the mixture was added1 N HCl (22.8 mL), and the mixture stirred at ambient temperatureovernight. The solids were collected by filtration, washed with water(2×4 mL) and dried in a vacuum oven at 45° C. overnights to give3-{[(3-fluorophenyl)amino]sulfonyl}benzoic acid: ¹H NMR (400 MHz,DMSO-d₆) δ ppm 13.51 (bs, 1H), 10.68 (bs, 1H), 8.30 (t, J=1.8, 1H), 8.14(dt, J=7.7, 1.4, 1H), 7.99 (ddd, J=7.8, 2.0, 1.1, 1H), 7.70 (t, J=7.8,1H), 7.27 (m, 1H), 6.94-6.82 (m, 3H); MS (ESI) m/z 294 (M−H)⁻.

Step C:

To 3-{[(3-fluorophenyl)amino]sulfonyl}benzoic acid (0.9 g, 3.05 mmol)and2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (1.27 g, 3.35 mmol) in N,N-dimethylacetamide (6.4mL) and 2-methyltetrahydrofuran (15 mL) was added(S)-octahydropyrrolo[1,2-a]pyrazine (0.55 g, 4.33 mmol) in2-methyltetrahydrofuran (4 mL). The reaction was stirred at ambienttemperature overnight and then diluted with 2-methyltetrahydrofuran (15mL). The organic solution was washed with 6% NaHCO₃/6% NaCl (10 mL), andthe aqueous layer was extracted with 2-methyltetrahydrofuran (15 mL).The combined organic layers were washed with 6% NaHCO₃/6% NaCl (10 mL),saturated NaCl (2×10 mL, 2×20 mL) and 1:1 saturated NaCl/water (2×20mL), and then concentrated. The residue was concentrated from ethanol(2×10 mL) to give the title compound.

Step D:

To the product of Step C was added ethanol (25 mL) and then concentratedHCl (0.29 g, 3.0 mmol) in ethanol (1 mL) dropwise over 1 minute. Themixture was stirred at ambient temperature overnight and concentrated toafford the title compound as the hydrochloride salt: ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm 7.95-7.78 (m, 2H), 7.75-7.58 (m, 2H), 7.34-7.17 (m,1H), 7.00-6.77 (m, 3H), 4.74 (br d, J=60.9, 1H), 4.04-2.81 (m, 8H),2.32-1.36 (m, 4H); MS (EST) m/z 402 (M+H)⁺.

Example 4N-(2,6-difluorophenyl)-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide

Step A:

To 3-(chlorosulfonyl)benzoyl chloride (0.474 g, 1.98 mmol) in anhydrousdichloromethane (10 mL) was added (S)-octahydropyrrolo[1,2-a]pyrazine(0.250 g, 1.98 mmol) in dichloromethane (4 mL) slowly over 10 minutes atroom temperature. Then sodium carbonate (0.420 g, 3.96 mmol) was added.The mixture was stirred at room temperature for 5 hours. Then2,6-difluoroaniline (2.56 g, 19.81 mmol) was added. The mixture wasstirred at room temperature overnight and then concentrated. The residuewas purified by chromatography on silica gel (dichloromethane, thenmethanol/dichloromethane=1:10) to give the title compound.

Step B:

To the material from Step A (230 mg, 0.546 mmol) was added 2 mL of 1 NHCl solution, and 1 mL of methanol. The solid was dissolved, and thenthe mixture was concentrated to dryness to give the titled compound asthe hydrochloride salt: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.71-1.95 (m,4H), 2.99 (m, 2H), 3.25 (m, 2H), 3.43 (m, 2H), 3.81 (m, 2H), 4.72 (m,1H), 7.13 (m, 2H), 7.38 (m, 1H), 7.75 (m, 3H), 10.35 (s, 1H), 11.46 (m,1H); MS (ESI) m/z 422 (M+H)⁺.

Example 5N-(4-fluorophenyl)-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide

The titled compound was prepared as the HCl salt using the proceduresdescribed in Example 4 substituting 4-fluoroaniline for2,6-difluoroaniline: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.15-2.05 (m, 8H),2.8-3.07 (m, 4H), 4.45 (m, 1H), 7.08 (m, 4H), 7.62 (m, 3H), 7.79 (m,1H), 10.25 (br s, 1H); MS (ESI) m/z 404 (M+H)⁺.

Example 63-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]-N-[3-(trifluoromethyl)phenyl]benzenesulfonamide

The titled compound was prepared using the procedure described inExample 4 Step A substituting 3-(trifluoromethyl)aniline for2,6-difluoroaniline: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.15-2.05 (m, 8H),2.75-3.02 (m, 4H), 4.46 (m, 1H), 7.42 (m, 4H), 7.66 (m, 3H), 7.84 (m,1H), 10.75 (br s, 1H); MS (ESI) m/z 454 (M+H)⁺.

Example 7N-(3-fluorophenyl)-3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide

The titled compound was prepared as the HCl salt using the proceduresdescribed in Example 1 substituting 3-fluoroaniline for4-(trifluoromethyl)aniline: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.65-2.10(m, 4H), 2.85-3.85 (m, 8H), 4.60-4.80 (m, 1H), 6.90 (m, 3H), 7.29 (m,1H), 7.68 (m, 2H), 7.90 (m, 2H), 10.85 (br s, 1H), 11.30 (m, 1H); MS(ESI) m/z 404 (M+H)⁺.

Example 83-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]-N-[4-(trifluoromethyl)phenyl]benzenesulfonamide

The titled compound was prepared using the procedure described inExample 4 Step A substituting 4-(trifluoromethyl)aniline for2,6-difluoroaniline: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.12-2.05 (m, 8H),2.77-3.15 (m, 4H), 4.46 (m, 1H), 7.29 (d, 2H, J=8 Hz), 7.63 (m, 4H),7.73 (s, 1H), 7.90 (m, 1H), 10.86 (br s, 1H); MS (ESI) m/z 454 (M+H)⁺.

Example 9N-(2-chlorophenyl)-3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide

The titled compound was prepared using the procedure described inExample 1, Step A substituting 2-chloroaniline for4-(trifluoromethyl)aniline: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.23-2.08(m, 8H), 2.79-3.02 (m, 4H), 4.47 (m, 1H), 7.30 (m, 4H), 7.67 (m, 3H),7.76 (s, 1H), 10.08 (br s, 1H); MS (ESI) m/z 420 (M+H)⁺.

Example 10N-(2-chlorophenyl)-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide

The titled compound was prepared using the procedure described inExample 4 Step A substituting 2-chloroaniline for 2,6-difluoroaniline:¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.22-2.05 (m, 8H), 2.79-3.02 (m, 4H),4.46 (m, 1H), 7.29 (m, 4H), 7.62 (m, 3H), 7.76 (s, 1H), 9.88 (br s, 1H);MS (ESI) m/z 420 (M+H)⁺.

Example 11N-(2,3-difluorophenyl)-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide

The titled compound was prepared using the procedure described inExample 4 Step A substituting 2,3-difluoroaniline for2,6-difluoroaniline: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.12-2.08 (m, 8H),2.58-3.12 (m, 4H), 4.48 (m, 1H), 7.13 (m, 4H), 7.65 (m, 3H), 7.81 (m,1H); MS (ESI) m/z 422 (M+H)⁺.

Example 12N-(2,5-difluorophenyl)-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide

The titled compound was prepared using the procedure described inExample 4 Step A substituting 2,5-difluoroaniline for2,6-difluoroaniline: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.30-2.30 (m, 8H),2.60-2.90 (m, 4H), 4.47 (m, 1H), 7.09 (m, 3H), 7.67 (m, 3H), 7.82 (m,1H); MS (ESI) m/z 422 (M+H)⁺.

Example 13N-(2,6-difluorophenyl)-3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide

Step A:

To ethyl 3-(chlorosulfonyl)benzoate (1.0 g, 4.02 mmol) inN,N-dimethylacetamide (6 mL) was added 2,6-difluoroaniline (2.03 g, 15.8mmol) dropwise at room temperature. The mixture was stirred at roomtemperature for 5 hours and then diluted with ethyl acetate (40 mL). Theorganic solution was washed with 1 N HCl (2×15 mL and 3×30 mL) andsaturated NaCl (30 mL). The organics were concentrated, ethanol (10 mL)was added, and the mixture was concentrated to give ethyl3-{[(2,6-difluorophenyl)amino]sulfonyl}benzoate.

Step B:

To the product of Step A was added ethanol (8 mL) followed by a solutionof 50% NaOH (0.96 g, 12.1 mmol) in water (8 mL). The reaction wasstirred at ambient temperature for 1.5 hours. To the mixture was addeddropwise 1 N HCl (28 mL), and the mixture was stirred at ambienttemperature overnight. The solids were collected by filtration, washedwith water (2×5 mL), and dried in a vacuum oven at 50° C. overnights togive 3-{[(2,6-difluorophenyl)amino]sulfonyl}benzoic acid: ¹H NMR (400MHz, DMSO-d₆) δ ppm 7.11 (t, J=8.1 Hz, 2H), 7.33-7.41 (m, 1H), 7.71 (t,J=7.7 Hz, 1H), 7.92 (dt, J=8.4, 1.1 Hz, 1H), 8.19 (dt, J=7.8, 1.1 Hz,1H), 8.27 (t, J=1.51 Hz, 1H), 10.20 (s, 1H), 13.48 (s, 1H); MS (ESI) m/z312 (M−H)⁻.

Step C:

To 3-{[(2,6-difluorophenyl)amino]sulfonyl}benzoic acid (0.96 g, 3.06mmol) and2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (1.28 g, 3.37 mmol) in N,N-dimethylacetamide (7.4mL) and 2-methyltetrahydrofuran (22 mL) was added(R)-octahydropyrrolo[1,2-a]pyrazine (0.54 g, 4.28 mmol). The reactionwas stirred at ambient temperature for 5.5 hours, and then it wasdiluted with 2-methyltetrahydrofuran (15 mL). The organic solution waswashed with 6% NaHCO₃/6% NaCl (35 mL), and the aqueous layer wasextracted with 2-methyltetrahydrofuran (50 mL). The organic layer waswashed with 6% NaHCO₃/6% NaCl (50 mL) and 1:1 saturated NaCl/water (6×15mL), and then it was concentrated. The residue was concentrated fromethanol (2×10 mL) to give the title compound.

Step D:

To the product of Step C was added ethanol (13 mL) and then concentratedHCl (0.47 g, 4.8 mmol) in ethanol (1 mL) dropwise over 1 minute. Themixture was stirred at ambient temperature overnight and concentrated toafford the title compound as the hydrochloride salt: ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.50-2.28 (m, 4H), 2.83-3.99 (m, 8H), 4.60-4.93 (br dJ=65 Hz, 1H), 7.08-7.13 (m, 2H), 7.34-7.41 (m, 1H), 7.66-7.83 (m, 4H),10.19 (s, 1H), 10.94-11.14 (m, 1H); MS (ESI) m/z 422 (M+H)⁺.

Example 14N-(2,3-difluorophenyl)-3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide

The titled compound was prepared using the procedure described inExample 1, Step A substituting 2,3-difluoroaniline for4-(trifluoromethyl)aniline: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.12-2.08(m, 8H), 2.58-3.12 (m, 4H), 4.48 (m, 1H), 7.13 (m, 3H), 7.65 (m, 3H),7.81 (m, 1H); MS (ESI) m/z 422 (M+H)⁺.

Example 15N-(2,5-difluorophenyl)-3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide

The titled compound was prepared using the procedure described inExample 1, Step A substituting 2,5-difluoroaniline for4-(trifluoromethyl)aniline: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.30-2.30(m, 8H), 2.60-2.90 (m, 4H), 4.47 (m, 1H), 7.09 (m, 3H), 7.67 (m, 3H),7.82 (m, 1H); MS (ESI) m/z 422 (M+H)⁺.

Example 16N-(2,4-difluorophenyl)-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide

The titled compound was prepared using the procedure described inExample 4 Step A substituting 2,4-difluoroaniline for2,6-difluoroaniline: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.26 (m, 2H), 1.67(m, 2H), 1.85 (m, 2H), 2.06 (m, 2H), 2.87 (m, 2H), 2.99 (m, 2H), 4.49(m, 1H), 7.05 (m, 1H), 7.24 (m, 2H), 7.63 (m, 3H), 7.75 (m, 1H); MS(ESI) m/z 422 (M+H)⁺.

Example 17N-(2-fluorophenyl)-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide

Step A:

To 3-(chlorosulfonyl)benzoyl chloride (0.521 g, 2.18 mmol) in anhydrousdichloromethane (10 mL) was added (S)-octahydropyrrolo[1,2-a]pyrazine(0.250 g, 1.98 mmol) in dichloromethane (4 mL) slowly over 10 minutes atroom temperature. The mixture was stirred at room temperature for 5hours. Then 2-fluoroaniline (1.54 g, 13.87 mmol) was added. The mixturewas stirred at room temperature overnight and then concentrated. Theresidue was purified by chromatography on silica gel (dichloromethane,then methanol/dichloromethane=1:10) to give the titled compound.

Step B:

To the product of Step A (339 mg, 0.84 mmol) was added 2 mL of 1 N HClsolution, and 1 mL of methanol. The mixture was stirred untilhomogeneous, and then the mixture was concentrated to dryness to givethe titled compound as the corresponding HCl salt: ¹H NMR (400 MHz,DMSO-d₆) δ 1.60 (m, 2H), 1.99 (m, 4H), 2.95 (m, 3H), 3.67 (m, 3H), 4.75(m, 1H), 7.19 (m, 4H), 7.75 (m, 4H), 10.25 (s, 1H), 11.35 (br s, 1H,HCl); MS (ESI): m/z 404 (M+H)⁺.

Example 18N-(2,4-difluorophenyl)-3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide

The titled compound was prepared using the procedure described inExample 1 Step A substituting 2,4-difluoroaniline for4-(trifluoromethyl)aniline: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.26 (m,2H), 1.67 (m, 2H), 1.85 (m, 2H), 2.06 (m, 2H), 2.87 (m, 2H), 2.99 (m,2H), 4.49 (m, 1H), 7.05 (m, 1H), 7.24 (m, 2H), 7.63 (m, 3H), 7.75 (m,1H); MS (ESI) m/z 422 (M+H)⁺.

Example 193-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]-N-[2-(trifluoromethyl)phenyl]benzenesulfonamide

The titled compound was prepared using the procedure described inExample 4 Step A substituting 2-(trifluoromethyl)aniline for2,6-difluoroaniline: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33-1.83 (m, 4H),2.14-2.25 (m, 4H), 2.65-3.07 (m, 4H), 4.46 (m, 1H), 7.14 (m, 1H), 7.27(m, 1H), 7.48 (m, 1H), 7.63 (m, 4H), 7.69 (s, 1H), 7.83 (m, 1H); MS(ESI) m/z 454 (M+H)⁺.

Example 204-chloro-2-fluoro-N-(2-fluorophenyl)-5-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide

Step A:

To Ethyl 2-chloro-5-(chlorosulfonyl)-4-fluorobenzoate (1.0 g, 3.32 mmol)in N,N-dimethylacetamide (5 mL) was added 2-fluoroaniline (1.48 g, 13.28mmol) dropwise over 30 seconds at room temperature. The mixture wasstirred at room temperature for 2 hours, and then it was diluted withethyl acetate (33 mL). The organic solution was washed with 1 N HCl(2×13 mL) and saturated NaCl (13 mL). The organic layer wasconcentrated, ethanol (8 mL) was added, and the mixture concentrated togive ethyl2-chloro-4-fluoro-5-{[(2-fluorophenyl)amino]sulfonyl}benzoate.

Step B:

To ethyl 2-chloro-4-fluoro-5-{[(2-fluorophenyl)amino]sulfonyl}benzoate(1.45 g) was added ethanol (6.4 mL) followed by a solution of NaOH(0.398 g, 9.96 mmol) in water (6.4 mL). The reaction was stirred atambient temperature for 1 hour. To the mixture was added 1 N HCl (22.8mL), and the mixture was stirred for 30 minutes. The solids werecollected by filtration, washed with water (2×4 mL), and dried in avacuum oven at 45° C. for 2.5 days to give2-chloro-4-fluoro-5-{[(2-fluorophenyl)amino]sulfonyl}benzoic acid: ¹HNMR (400 MHz, DMSO-d₆) δ ppm 13.89 (s, 1H), 10.67 (s, 1H), 8.09 (d,J=7.7, 1H), 7.88 (d, J=9.9, 1H), 7.32-7.11 (m, 4H); MS (ESI) m/z 346(M−H)⁻.

Step C:

To 2-chloro-4-fluoro-5-{[(2-fluorophenyl)amino]sulfonyl}benzoic acid(0.9 g, 2.59 mmol) and2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (1.08 g, 2.85 mmol) in N,N-dimethylacetamide (6.4mL) and 2-methyltetrahydrofuran (15 mL) was added(R)-octahydropyrrolo[1,2-a]pyrazine (0.46 g, 3.68 mmol) in2-methyltetrahydrofuran (4 mL). The reaction was stirred at ambienttemperature overnight and diluted with 2-methyltetrahydrofuran (15 mL).The organic solution was washed with 6% NaHCO₃/6% NaCl (10 mL), and theaqueous layer was extracted with 2-methyltetrahydrofuran (15 mL). Thecombined organic layers were washed with 6% NaHCO₃/6% NaCl (10 mL) andsaturated NaCl (2×10 mL), and then concentrated. The residue wasconcentrated from ethanol (2×10 mL) to give the title compound.

Step D:

To the product of Step C was added ethanol (25 mL) and then concentratedHCl (0.29 g, 3.0 mmol) in ethanol (1 mL) dropwise over 1 minute. Themixture was stirred at ambient temperature for 30 minutes, and thesolids were collected by filtration. The product was washed with ethanoland dried in a vacuum oven at room temperature to give the hydrochloridesalt of the title compound: ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ ppm8.28-7.65 (m, 2H), 7.50-7.07 (m, 4H), 4.71 (br d, J=65.4, 1H), 4.2-2.8(m, 8H), 2.33-1.38 (m, 4H); MS (ESI) m/z 456 (M+H)⁺. Diffractionpatterns were collected at ambient conditions in reflection mode usingCu-Kα1 (λ=1.54060 Å) radiation. The diffractometer is equipped with aposition sensitive detector that is calibrated at 1 degree intervalsusing the direct beam. Calibration is verified with a NIST standard.Main characteristic diffraction peak positions (degrees 2-theta ±0.1)based on a diffraction pattern collected under aforementioned conditionsare as follows: 8.0, 14.9, 15.7, 16.4, 21.0, 22.0, 22.8.

Example 21N-(3-chlorophenyl)-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide

The titled compound was prepared using the procedure described inExample 4 Step A substituting 3-chloroaniline for 2,6-difluoroaniline:¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.27-2.05 (m, 8H), 2.80-3.15 (m, 4H),4.49 (m, 1H), 7.08 (m, 3H), 7.27 (m, 1H), 7.66 (m, 3H), 7.85 (m, 1H),10.61 (br s, 1H); MS (ESI) m/z 422 (M+H)⁺.

Example 22(8aR)-2-[3-({4-[bis(4-fluorophenyl)methyl]piperazin-1-yl}sulfonyl)benzoyl]octahydropyrrolo[1,2-a]pyrazine

The titled compound was prepared using the procedure described inExample 1 Step A substituting 1-(bis(4-fluorophenyl)methyl)piperazine (1equivalent) for 4-(trifluoromethyl)aniline: ¹H NMR (500 MHz, DMSO-d₆) δppm 1.20-1.40 (m, 2H), 1.60 (m, 3H), 1.80-2.20 (3H), 2.35 (m, 4H),2.90-3.10 (m, 8H), 3.20 (m, 1H), 4.45-4.60 (m, 1H), 7.10 (m, 4H), 7.39(m, 4H), 7.63 (br s, 1H), 7.80 (m, 3H); MS (ESI) m/z 581 (M+H)⁺.

Example 23(8aS)-2-[3-({4-[bis(4-fluorophenyl)methyl]piperazin-1-yl}sulfonyl)benzoyl]octahydropyrrolo[1,2-a]pyrazine

The titled compound was prepared using the procedure described inExample 4 Step A substituting 1-(bis(4-fluorophenyl)methyl)piperazine (1equivalent) for 2,6-difluoroaniline: ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.59 (m, 2H), 1.69 (m, 2H), 1.91 (m, 2H), 2.07 (m, 2H), 2.33 (m, 4H),2.93 (m, 4H), 3.02 (m, 2H), 3.52 (m, 2H), 4.39 (s, 1H), 4.49 (m, 1H),7.08 (t, 4H, J=8 Hz), 7.37 (t, 4H, J=8 Hz), 7.66 (s, 1H), 7.77 (m, 2H),7.80 (m, 1H); MS (ESI) m/z 581 (M+H)⁺.

Example 24(8aR)-2-{3-[(4-benzhydrylpiperazin-1-yl)sulfonyl]benzoyl}octahydropyrrolo[1,2-a]pyrazine

The titled compound was prepared using the procedure described inExample 1 Step A substituting 1-benzhydrylpiperazine (1 equivalent) for4-(trifluoromethyl)aniline: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.20-1.40(m, 2H), 1.63 (m, 3H), 1.80-2.16 (3H), 2.35 (m, 4H), 2.92-3.20 (m, 8H),3.40-3.55 (m, 1H), 4.45-4.62 (m, 1H), 7.15 (m, 2H), 7.25 (m, 4H), 7.38(m, 4H), 7.62 (br s, 1H), 7.80 (m, 3H); MS (ESI) m/z 545 (M+H)⁺.

Example 25N-(3-chlorophenyl)-3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide

The titled compound was prepared using the procedure described inExample 1 Step A substituting 3-chloroaniline for4-(trifluoromethyl)aniline: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.27-2.05(m, 8H), 2.80-3.15 (m, 4H), 4.49 (m, 1H), 7.08 (m, 3H), 7.27 (m, 1H),7.66 (m, 3H), 7.85 (m, 1H), 10.61 (br s, 1H); MS (ESI) m/z 421 (M+H)⁺.

Example 26N-(2,2-diphenylethyl)-3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide

The titled compound was prepared using the procedure described inExample 1 Step A substituting 2,2-diphenylethanamine (1 equivalent) for4-(trifluoromethyl)aniline: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.10 (m,1H), 1.36 (m, 1H), 1.50-1.90 (m, 5H), 1.95-2.15 (3H), 2.80-3.40 (4H),3.98 (t, 1H, J=8 Hz), 4.46-4.58 (m, 1H), 7.16 (m, 2H), 7.26 (m, 8H),7.63 (m, 2H), 7.72 (br s, 1H), 7.82 (m, 2H); MS (ESI) m/z 490 (M+H)⁺.

Example 273-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]-N-[2-(trifluoromethyl)phenyl]benzenesulfonamide

The titled compound was prepared using the procedure described inExample 1 Step A substituting 2-(trifluoromethyl)aniline for4-(trifluoromethyl)aniline: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33-1.83(m, 4H), 2.14-2.25 (m, 4H), 2.65-3.07 (m, 4H), 4.46 (m, 1H), 7.14 (m,1H), 7.27 (m, 1H), 7.48 (m, 1H), 7.63 (m, 4H), 7.69 (s, 1H), 7.83 (m,1H); MS (ESI) m/z 454 (M+H)⁺.

Example 28(8aS)-2-{3-[(4-benzhydrylpiperazin-1-yl)sulfonyl]benzoyl}octahydropyrrolo[1,2-a]pyrazine

The titled compound was prepared using the procedure described inExample 4 Step A substituting 1-benzhydrylpiperazine (1 equivalent) for2,6-difluoroaniline: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.27 (m, 2H), 1.63(m, 2H), 1.91 (m, 2H), 2.08 (m, 2H), 2.37 (m, 4H), 2.94 (m, 4H), 3.02(m, 2H), 3.54 (m, 2H), 4.30 (s, 1H), 4.53 (m, 1H), 7.16 (t, 2H, J=8 Hz),7.24 (t, 4H, J=8 Hz), 7.35 (d, 4H, J=8 Hz), 7.66 (s, 1H), 7.77 (m, 2H),7.80 (m, 1H); MS (ESI) m/z 545 (M+H)⁺.

Example 29N-(3,3-diphenylpropyl)-3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide

The titled compound was prepared using the procedure described inExample 1 Step A substituting 3,3-diphenylpropan-1-amine (1 equivalent)for 4-(trifluoromethyl)aniline: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.15 (m,1H), 1.38 (m, 1H), 1.50-1.90 (m, 5H), 1.96-2.10 (m, 3H), 2.62 (m, 2H),2.78-3.10 (m, 3H), 3.42 (m, 1H), 3.97 (t, 1H, J=8 Hz), 4.46-4.58 (m,1H), 7.16-7.26 (m, 10H), 7.62 (m, 2H), 7.70 (br s, 1H), 7.80 (m, 2H); MS(ESI) m/z 504 (M+H)⁺.

Example 30N-(3,3-diphenylpropyl)-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide

The titled compound was prepared using the procedure described inExample 4 Step A substituting 3,3-diphenylpropan-1-amine (1 equivalent)for 2,6-difluoroaniline: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.25 (m, 2H),1.68 (m, 2H), 1.85 (m, 2H), 2.03 (m, 2H), 2.11 (m, 2H), 2.66 (m, 2H),2.99 (m, 2H), 3.09 (m, 2H), 3.97 (m, 1H), 4.52 (m, 1H), 7.14 (t, 2H, J=8Hz), 7.19 (d, 4H, J=8 Hz), 7.24 (t, 4H, J=8 Hz), 7.65 (m, 2H), 7.70 (s,1H), 7.80 (m, 2H); MS (ESI) m/z 504 (M+H)⁺.

Example 31N-(2,2-diphenylethyl)-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide

The titled compound was prepared using the procedure described inExample 4 Step A substituting 2,2-diphenylethanamine (1 equivalent) for2,6-difluoroaniline: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.37 (m, 2H), 1.53(m, 2H), 1.83 (m, 2H), 2.03 (m, 2H), 2.84 (m, 2H), 2.99 (m, 2H), 3.39(m, 2H), 4.10 (m, 1H), 4.52 (m, 1H), 7.18 (m, 2H), 7.29 (m, 8H), 7.64(m, 2H), 7.74 (s, 1H), 7.83 (m, 2H); MS (ESI) m/z 490 (M+H)⁺.

Example 324-chloro-3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]-N-[4-(trifluoromethyl)phenyl]benzenesulfonamide

To 2-chloro-5-(chlorosulfonyl)benzoic acid (0.51 g, 2.0 mmol) was addeddichloromethane (10 mL), oxalyl chloride (1.5 mL) and one small drop ofN,N-dimethylformamide. The mixture was stirred at room temperature for 3days. The mixture was then concentrated until oxalyl chloride was goneto give 2-chloro-5-(chlorosulfonyl)benzoyl chloride. The residue wasused without purification.

To crude 2-chloro-5-(chlorosulfonyl)benzoyl chloride (2 mmol) inanhydrous dichloromethane (50 mL) was added(R)-octahydropyrrolo[1,2-a]pyrazine (0.252 g, 2 mmol) in dichloromethane(4 mL) slowly over 10 minutes at room temperature. Then sodium carbonate(0.46 g, 4.4 mmol) was added. The mixture was stirred at roomtemperature overnight. Then dichloromethane was removed byconcentration, and 4-(trifluoromethyl)aniline (3.22 g, 20 mmol) wasadded. The mixture was stirred at 70° C. overnight. Then sodiumcarbonate (0.21 g, 2 mmol) and methanol (5 mL) were added at roomtemperature. The mixture was stirred for 30 minutes, then filtered, andconcentrated. The residue was purified by chromatography on silica gel(ethyl acetate, then methanol/ethyl acetate=1:10) to give the titledcompound: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.30 (m, 1H), 1.55 (m, 1H),1.70-2.00 (m, 4H), 2.60 (m, 2H), 2.80-3.50 (m, 4H), 4.40-4.60 (m, 1H),7.30 (m, 2H), 7.62 (m, 2H), 7.82 (m, 3H), 11.00 (br s, 1H); MS (ESI) m/z488 (M+H)⁺.

Example 33N-[2-(4-fluorophenyl)ethyl]-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide

The titled compound was prepared using the procedure described inExample 4 Step A substituting 2-(4-fluorophenyl)ethanamine (1equivalent) for 2,6-difluoroaniline: ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.24 (m, 2H), 1.64 (m, 2H), 1.86 (m, 2H), 2.06 (m, 2H), 2.67 (m, 2H),2.88 (m, 2H), 2.98 (m, 2H), 3.43 (m, 2H), 4.52 (m, 1H), 7.07 (t, 2H, J=8Hz), 7.19 (t, 2H, J=8 Hz), 7.65 (m, 2H), 7.74 (s, 1H), 7.82 (m, 2H); MS(ESI) m/z 432 (M+H)⁺.

Example 342-chloro-5-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]-N-[4-(trifluoromethyl)phenyl]benzenesulfonamide

The titled compound was prepared using the procedure described inExample 32 substituting 4-chloro-3-(chlorosulfonyl)benzoic acid for2-chloro-5-(chlorosulfonyl)benzoic acid: ¹H NMR (500 MHz, DMSO-d₆) δ ppm1.40-1.60 (m, 2H), 1.80-2.05 (m, 4H), 2.75 (m, 2H), 2.95-3.50 (m, 4H),4.20-4.45 (m, 1H), 7.30 (d, 2H, J=8 Hz), 7.62 (d, 2H, J=8 Hz), 7.78 (m,2H), 8.15 (s, 1H), 11.10 (br s, 1H); MS (ESI) m/z 488 (M+H)⁺.

Example 35(8aS)-2-(3-{[4-(4-fluorophenyl)piperazin-1-yl]sulfonyl}benzoyl)octahydropyrrolo[1,2-a]pyrazine

The titled compound was prepared using the procedure described inExample 4 Step A substituting 1-(4-fluorophenyl)piperazine (1equivalent) for 2,6-difluoroaniline: ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.20 (m, 2H), 1.63 (m, 2H), 1.86 (m, 2H), 2.07 (m, 2H), 2.88 (m, 2H),2.93 (m, 2H), 3.06 (m, 4H), 3.14 (m, 4H), 4.52 (m, 1H), 6.93 (m, 2H),7.04 (m, 2H), 7.72 (s, 1H), 7.75 (m, 2H), 7.85 (m, 1H); MS (ESI) m/z 473(M+H)⁺.

Example 36N-1,1′-biphenyl-2-yl-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide

The titled compound was prepared using the procedure described inExample 4 Step A substituting biphenyl-2-amine for 2,6-difluoroaniline:¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.26 (m, 2H), 1.67 (m, 2H), 1.83 (m,2H), 2.05 (m, 2H), 2.85 (m, 2H), 2.99 (m, 2H), 4.50 (m, 1H), 7.04 (m,1H), 7.28 (m, 8H), 7.57 (m, 4H), 9.65 (s, 1H); MS (ESI) m/z 462 (M+H)⁺.

Example 373-(octahydro-2H-pyrido[1,2-a]pyrazin-2-ylcarbonyl)-N-[4-(trifluoromethyl)phenyl]benzenesulfonamide

Step A:

To ethyl 3-(chlorosulfonyl)benzoate (4.0 g, 16.08 mmol) inN,N-dimethylacetamide (20 mL) was added 4-(trifluoromethyl)aniline(10.37 g, 64.3 mmol) dropwise at room temperature. The mixture wasstirred at room temperature for 2.5 hours, and then it was diluted withethyl acetate (130 mL). The organic solution was washed with 1 N HCl(2×60 mL) and saturated NaCl (60 mL). The organic layer wasconcentrated, ethanol (40 mL) was added, and the mixture wasconcentrated to give ethyl 341[4-(tri fluoromethyl)phenyl]amino 1sulfonyl)benzoate.

Step B:

To the product of Step A was added ethanol (25 mL) followed by asolution of NaOH (1.93 g, 48.3 mmol) in water (25 mL). The reaction wasstirred at ambient temperature for 1.5 hours. To the mixture was addeddropwise 1 N HCl (95 mL), and the mixture was stirred at ambienttemperature overnight. The solids were collected by filtration, washedwith water (2×20 mL), and dried in a vacuum oven at 45° C. overnights togive 3-({[4-(trifluoromethyl)phenyl]amino}sulfonyl)benzoic acid: ¹H NMR(400 MHz, DMSO-d₆) δ ppm 7.28 (d, J=8.4 Hz, 2H), 7.62 (d, J=8.5 Hz, 2H),7.71 (t, J=7.8 Hz, 1H), 8.03 (ddd, J=7.8, 1.9, 1.1 Hz, 1H), 8.15 (dt,J=7.8, 1.4 Hz, 1H), 8.34 (t, J=1.7 Hz, 1H), 10.98 (s, 1H), 13.54 (s,1H); MS (EST) m/z 344 (M−H)⁻.

Step C:

To 3-({[4-(trifluoromethyl)phenyl]amino}sulfonyl)benzoic acid (4.35 g,12.6 mmol) and2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (5.27 g, 13.9 mmol) in N,N-dimethylacetamide (30mL) and 2-methyltetrahydrofuran (90 mL) was added1,4-diazabicyclo[4.4.0]decane (2.47 g, 17.6 mmol). The reaction wasstirred at ambient temperature for 2.5 hours, and then it was dilutedwith 2-methyltetrahydrofuran (57 mL). The organic solution was washedwith 6% NaHCO₃/6% NaCl (35 mL), and the aqueous layer was extracted with2-methyltetrahydrofuran (50 mL). The organic layer was washed with 6%NaHCO₃/6% NaCl (50 mL) and 1:1 saturated NaCl/water (6×50 mL), and thenit was concentrated. The residue was concentrated from ethanol (2×50 mL)to give the title compound.

Step D:

To the product of Step C was added ethanol (100 mL) and thenconcentrated HCl (1.6 g, 16.2 mmol) in ethanol (2 mL) dropwise over 1minute. The mixture was stirred at ambient for 4.5 hours. The solidswere collected by filtration, washed with ethanol (15 mL), and driedovernight at 55° C. to yield the title compound as the hydrochloridesalt: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.23-1.99 (m, 6H), 2.79-3.65 (m,8H), 4.53 (s, 1H), 7.31 (d, J=8.4 Hz, 2H), 7.61 (d, J=8.4 Hz, 2H),7.66-7.72 (m, 2H), 7.91-7.93 (m, 2H), 11.07 (s, 2H); MS (ESI) m/z 468(M+H)⁺. Diffraction patterns were collected at ambient conditions inreflection mode using Cu-Kα1 (λ=1.54060 Å) radiation. The diffractometeris equipped with a position sensitive detector that is calibrated at 1degree intervals using the direct beam. Calibration is verified with aNIST standard. Main characteristic diffraction peak positions (degrees2-theta ±0.1) based on a diffraction pattern collected underaforementioned conditions are as follows: 6.2, 12.8, 15.2, 15.7, 17.5,18.8, 20.3.

Example 383-(octahydro-2H-pyrido[1,2-a]pyrazin-2-ylcarbonyl)-N-[3-(trifluoromethyl)phenyl]benzenesulfonamide

To 3-(chlorosulfonyl)benzoyl chloride (0.36 g 1.5 mmol) in anhydrousdichloromethane (50 mL) was added octahydro-1H-pyrido[1,2-a]pyrazine(0.21 g, 1.5 mmol) in dichloromethane (4 mL) slowly over 10 minutes atroom temperature. Then sodium carbonate (0.32 g, 3 mmol) was added. Themixture was stirred at room temperature for 5 hours. Then3-(trifluoromethyl)aniline (2.9 g, 18 mmol) was added. The mixture wasstirred at room temperature for 5 days, then sodium carbonate (0.32 g, 3mmol) and methanol (5 mL) were added, the mixture was stirred for 20minutes, then filtered, and concentrated. The residue was purified bychromatography on silica gel (methanol/ethyl acetate=1:10) to give thetitled compound: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.00-1.27 (m, 3H),1.42-2.10 (m, 7H), 2.70-3.40 (m, 4H), 4.25-4.40 (m, 1H), 7.40 (m, 3H),7.50 (m, 1H), 7.70 (m, 3H), 7.85 (m, 1H), 10.80 (br s, 1H); MS (ESI) m/z468 (M+H)⁺.

Example 39N-(2-fluorophenyl)-3-(octahydro-2H-pyrido[1,2-a]pyrazin-2-ylcarbonyl)benzenesulfonamide

The titled compound was prepared using the procedure described inExample 38 substituting 2-fluoroaniline for 4-(trifluoromethyl)aniline:¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.05-1.30 (m, 3H), 1.45-1.70 (m, 4H),1.80-2.10 (m, 3H), 2.70-3.40 (m, 4H), 4.30-4.40 (m, 1H), 7.17 (m, 2H),7.22 (m, 2H), 7.63 (m, 3H), 7.80 (br s, 1H), 10.20 (br s, 1H); MS (ESI)m/z 418 (M+H)⁺.

Example 40N-(4-fluorophenyl)-3-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]benzenesulfonamide

To 3-(chlorosulfonyl)benzoyl chloride (0.178 g, 0.746 mmol) in anhydrousdichloromethane (10 mL) was added 4-(pyrrolidin-1-yl)piperidine (0.115g, 0.746 mmol) in dichloromethane (4 mL) slowly over 10 minutes at roomtemperature. Then sodium carbonate (0.277 g, 2.61 mmol) was added. Themixture was stirred at room temperature for 5 hours. Then4-fluoroaniline (0.83 g, 7.5 mmol) was added. The mixture was stirred atroom temperature overnight. Then methanol (5 mL) was added, the mixturewas stirred for 20 minutes, then filtered, and concentrated. The residuewas purified by chromatography on silica gel (ethyl acetate, thenmethanol/ethyl acetate=1:10) to give the titled compound: ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.37 (m, 2H), 1.73 (m, 6H), 1.93 (m, 2H), 2.63 (m,4H), 2.96 (m, 2H), 4.25 (m, 1H), 7.08 (m, 4H), 7.62 (m, 3H), 7.79 (m,1H); MS (ESI) m/z 432 (M+H)⁺.

Example 41N-phenyl-3-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]benzenesulfonamide

The titled compound was prepared using the procedure described inExample 40 substituting aniline for 4-fluoroaniline: ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.38 (m, 2H), 1.74 (m, 6H), 1.93 (m, 2H), 2.74 (m, 4H),2.93 (m, 2H), 4.25 (m, 1H), 7.07 (m, 3H), 7.23 (m, 2H), 7.62 (m, 3H),7.81 (s, 1H); MS (ESI) m/z 414 (M+H)⁺.

Example 423-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]-N-[4-(trifluoromethyl)phenyl]benzenesulfonamide

The titled compound was prepared using the procedure described inExample 40 substituting 4-(trifluoromethyl)aniline for 4-fluoroaniline:¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.37 (m, 2H), 1.74 (m, 6H), 1.93 (m,2H), 2.66 (m, 4H), 2.9 (m, 2H), 4.28 (m, 1H), 7.24 (m, 2H), 7.62 (m,5H), 7.75 (m, 1H); MS (ESI) m/z 482 (M+H)⁺.

Example 433-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]-N-[3-(trifluoromethyl)phenyl]benzenesulfonamide

The titled compound was prepared using the procedure described inExample 40 substituting 3-(trifluoromethyl)aniline for 4-fluoroaniline:¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.51 (m, 2H), 1.84 (m, 6H), 2.07 (m,2H), 2.86 (m, 4H), 3.05 (m, 2H), 4.43 (m, 1H), 7.44 (m, 4H), 7.68 (m,3H), 7.87 (m, 1H), 10.81 (br s, 1H, NH); MS (ESI) m/z 482 (M+H)⁺.

Example 44N-(3-fluorophenyl)-3-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]benzenesulfonamide

The titled compound was prepared using the procedure described inExample 40 substituting 3-fluoroaniline for 4-fluoroaniline: ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.60 (m, 2H), 1.88 (m, 6H), 2.07 (m, 2H), 2.84 (m,4H), 3.07 (m, 2H), 4.43 (m, 1H), 6.91 (m, 3H), 7.29 (m, 1H), 7.65 (m,2H), 7.74 (s, 1H), 7.87 (m, 1H), 10.85 (br s, 1H NH); MS (ESI) m/z 432(M+H)⁺.

Example 45N-(2-fluorophenyl)-3-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]benzenesulfonamide

The titled compound was prepared as the HCl salt using first theprocedure described in Example 40 substituting 2-fluoroaniline for4-fluoroaniline and then the procedure described in Example 1 Step B: ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.61 (m, 2H), 1.89 (m, 6H), 2.10 (m, 2H),2.80 (m, 4H), 3.04 (m, 2H), 4.48 (m, 1H), 7.19 (m, 4H), 7.65 (m, 3H),7.79 (m, 1H), 10.25 (s, 1H), 11.09 (m, 1H); MS (ESI) m/z 432 (M+H)±.

Example 463-(1,4′-bipiperidin-1′-ylcarbonyl)-N-(4-fluorophenyl)benzenesulfonamide

To 3-(chlorosulfonyl)benzoyl chloride (0.359 g, 1.5 mmol) in anhydrousdichloromethane (80 mL) was added 1,4′-bipiperidine (0.252 g, 1.5 mmol)in dichloromethane (4 mL) slowly over 10 minutes at room temperature.Then sodium carbonate (0.32 g, 3 mmol) was added. The mixture wasstirred at room temperature for 5 hours. Then 4-fluoroaniline (1.167 g,10.5 mmol) was added. The mixture was stirred at room temperature for 3days, then sodium carbonate (0.32 g, 3 mmol) and methanol (5 mL) wereadded. The mixture was stirred for 20 minutes, then filtered, andconcentrated. The residue was purified by chromatography on silica gel(ethyl acetate, then methanol/ethyl acetate=1:10) to give the titledcompound: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.40-1.90 (m, 10H), 2.60-3.40(m, 8H), 4.45 (m, 1H), 7.08 (m, 4H), 7.62 (m, 3H), 7.78 (m, 1H); MS(ESI) m/z 446 (M+H)⁺.

Example 473-(1,4′-bipiperidin-1′-ylcarbonyl)-N-(2-fluorophenyl)benzenesulfonamide

The titled compound was prepared using the procedure described inExample 46 substituting 2-fluoroaniline for 4-fluoroaniline: ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.35-1.90 (m, 10H), 2.50-3.30 (m, 8H), 4.43 (m, 1H),7.10 (m, 3H), 7.22 (m, 1H), 7.60 (m, 3H), 7.79 (m, 1H); MS (ESI) m/z 446(M+H)⁺.

Example 483-(1,4′-bipiperidin-1′-ylcarbonyl)-N-(3-fluorophenyl)benzenesulfonamide

The titled compound was prepared using the procedure described inExample 46 substituting 3-fluoroaniline for 4-fluoroaniline: ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.30-1.90 (m, 10H), 2.50-3.20 (m, 8H), 4.42 (m, 1H),6.82 (m, 3H), 7.21 (m, 1H), 7.63 (m, 3H), 7.82 (m, 1H); MS (ESI) m/z 446(M−H)⁺.

Example 493-(1,4′-bipiperidin-1′-ylcarbonyl)-N-[4-(trifluoromethyl)phenyl]benzenesulfonamide

The titled compound was prepared using the procedure described inExample 46 substituting 4-(trifluoromethyl)aniline for 4-fluoroaniline:¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.30-1.85 (m, 10H), 2.50-3.15 (m, 8H),4.46 (m, 1H), 7.20 (d, 2H, J=8 Hz), 7.57 (d, 2H, J=8 Hz), 7.62 (m, 2H),7.72 (s, 1H), 7.85 (m, 1H); MS (ESI) m/z 496 (M+H)⁺.

Example 50(8aR)-2-{[3-({4-[bis(4-fluorophenyl)methyl]piperazin-1-yl}carbonyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine

To 3-(chlorosulfonyl)benzoyl chloride (0.359 g, 1.5 mmol) in anhydrousdichloromethane (40 mL) was added1-(bis(4-fluorophenyl)methyl)piperazine (0.433 g, 1.5 mmol) indichloromethane (4 mL) slowly over 10 minutes at room temperature. Thensodium carbonate (0.64 g, 6 mmol) was added. The mixture was stirred atroom temperature overnight. Then (R)-octahydropyrrolo[1,2-a]pyrazine(0.208 g, 1.65 mmol) was added. The mixture was stirred at reflux for 20minutes, and then at room temperature for 3 days. Methanol (5 mL) wasadded, the mixture was stirred for 20 minutes, then filtered, andconcentrated. The residue was purified by chromatography on silica gel(ethyl acetate/methanol=20:1) to give the titled compound: ¹H NMR (500MHz, DMSO-d₆) δ ppm 1.09 (m, 1H), 1.55 (m, 2H), 1.72 (m, 1H), 1.90 (m,4H), 2.10 (m, 1H), 2.20-2.50 (m, 6H), 2.90 (m, 2H), 3.58-3.78 (m, 4H),4.42 (s, 1H), 7.12 (m, 4H), 7.42 (m, 4H), 7.71 (m, 3H), 7.80 (m, 1H); MS(ESI) m/z 581 (M+H)⁺.

Example 51(8aS)-2-{[3-({4-[bis(4-fluorophenyl)methyl]piperazin-1-yl}carbonyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine

To 3-(chlorosulfonyl)benzoyl chloride (0.474 g, 1.981 mmol) in anhydrousdichloromethane (40 mL) was added1-(bis(4-fluorophenyl)methyl)piperazine (0.571 g, 1.981 mmol) indichloromethane (4 mL) slowly over 10 minutes at room temperature. Thensodium carbonate (0.64 g, 6 mmol) was added. The mixture was stirred atroom temperature overnight. Then (S)-octahydropyrrolo[1,2-a]pyrazine(0.250 g, 1.981 mmol) was added. The mixture was stirred at reflux for20 minutes and then at room temperature for 3 days. Methanol (5 mL) wasadded, the mixture was stirred for 20 minutes, then filtered, andconcentrated. The residue was purified by chromatography on silica gel(ethyl acetate/methanol=20:1) to give the titled compound: ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.07 (m, 1H), 1.55 (m, 2H), 1.71 (m, 1H), 1.95 (m,4H), 2.08 (m, 1H), 2.28 (m, 3H), 2.39 (m, 3H), 2.85 (m, 1H), 2.92 (m,1H), 3.57 (m, 2H), 3.74 (m, 2H), 4.45 (s, 1H), 7.13 (m, 4H), 7.45 (m,4H), 7.66 (s, 1H), 7.70 (m, 2H), 7.80 (m, 1H); MS (ESI) m/z 581 (M+H)⁺.

Example 52(8aR)-2-({3-[(4-benzhydrylpiperazin-1-yl)carbonyl]phenyl}sulfonyl)octahydropyrrolo[1,2-a]pyrazine

The titled compound was prepared using the procedure described inExample 50 substituting 1-benzhydrylpiperazine for1-(bis(4-fluorophenyl)methyl)piperazine: ¹H NMR (500 MHz, DMSO-d₆) δ ppm1.07 (m, 1H), 1.57 (m, 2H), 1.72 (m, 1H), 1.92 (m, 4H), 2.09 (m, 1H),2.25-2.50 (m, 6H), 2.90 (m, 2H), 3.60-3.78 (m, 4H), 4.39 (s, 1H), 7.18(m, 2H), 7.30 (m, 4H), 7.62 (m, 4H), 7.70 (m, 3H), 7.80 (m, 1H); MS(ESI) m/z 545 (M+H)⁺.

Example 53N-(2,2-diphenylethyl)-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylsulfonyl]benzamide

The titled compound was prepared using the procedure described inExample 51 substituting 2,2-diphenylethanamine for1-(bis(4-fluorophenyl)methyl)piperazine: ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.20 (m, 1H), 1.61 (m, 2H), 1.75 (m, 1H), 1.98 (m, 4H), 2.10 (m, 1H),2.25 (m, 1H), 2.92 (m, 2H), 3.54 (m, 1H), 3.71 (m, 1H), 3.92 (m, 1H),4.43 (m, 1H), 7.19 (m, 2H), 7.32 (m, 8H), 7.70 (m, 1H), 7.84 (m, 1H),8.00 (m, 2H), 8.83 (m, 1H); MS (ESI) m/z 490 (M+H)⁺.

Example 54(8aS)-2-({3-[(4-benzhydrylpiperazin-1-yl)carbonyl]phenyl}sulfonyl)octahydropyrrolo[1,2-a]pyrazine

The titled compound was prepared using the procedure described inExample 51 substituting 1-benzhydrylpiperazine for1-(bis(4-fluorophenyl)methyl)piperazine: ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.10 (m, 1H), 1.46 (m, 1H), 1.56 (m, 2H), 1.92 (m, 2H), 2.12 (m, 1H),2.22 (m, 1H), 2.56 (m, 1H), 2.81 (m, 2H), 3.76 (m, 1H), 3.98 (m, 9H),4.36 (s, 1H), 7.17 (m, 2H), 7.29 (m, 2H), 7.52 (m, 4H), 7.72 (m, 1H),7.97 (m, 1H), 8.16 (m, 1H), 8.65 (m, 3H); MS (ESI) m/z 545 (M+H)⁺.

Example 55N-(3,3-diphenylpropyl)-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylsulfonyl]benzamide

The titled compound was prepared using the procedure described inExample 51 substituting 3,3-diphenylpropan-1-amine for1-(bis(4-fluorophenyl)methyl)piperazine: 1H NMR (400 MHz, DMSO-d₆) δ ppm1.21 (m, 1H), 1.61 (m, 2H), 1.76 (m, 1H), 2.03 (m, 4H), 2.34 (m, 3H),2.93 (m, 2H), 3.22 (m, 2H), 3.61 (m, 1H), 3.76 (m, 1H), 4.04 (m, 1H),7.18 (m, 2H), 7.32 (m, 8H), 7.75 (m, 1H), 7.88 (m, 1H), 8.16 (m, 2H),8.88 (m, 1H); MS (ESI) m/z 504 (M+H)⁺.

Example 56N-[2-(4-fluorophenyl)ethyl]-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylsulfonyl]benzamide

The titled compound was prepared using the procedure described inExample 51 substituting 2-(4-fluorophenyl)ethanamine for1-(bis(4-fluorophenyl)methyl)piperazine: ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.22 (m, 1H), 1.62 (m, 2H), 1.77 (m, 1H), 2.03 (m, 4H), 2.32 (m, 1H),2.91 (m, 4H), 3.49 (m, 2H), 3.62 (m, 1H), 3.76 (m, 1H), 7.10 (dd, 2H,J=8, 9 Hz), 7.28 (dd, 2H, J=8, 11 Hz), 7.74 (m, 1H), 7.89 (m, 1H), 8.13(m, 2H), 8.85 (m, 1H); MS (ESI) m/z 432 (M+H)⁺.

Example 573-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]-N-[(1S)-2-hydroxy-1-phenylethyl]benzenesulfonamide

To 3-(chlorosulfonyl)benzoyl chloride (0.359 g, 1.5 mmol) in anhydrousdichloromethane (40 mL) was added (R)-octahydropyrrolo[1,2-a]pyrazine(0.189 g, 1.5 mmol) in dichloromethane (4 mL) slowly over 10 min at roomtemperature. Then sodium carbonate (0.48 g, 4.52 mmol) was added. Themixture was stirred at room temperature overnight. Then(S)-2-amino-2-phenylethanol (0.274 g, 2.0 mmol) in N,N-dimethylformamide(10 mL) was added. The mixture was stirred at room temperature for 4days. Then methanol (5 mL) was added, the mixture was stirred for 20minutes, then filtered, and concentrated. The residue was purified bychromatography on silica gel (methanol/dichloromethane=1:12) to give thetitled compound: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.30 (m, 1H), 1.60-2.10(m, 6H), 2.80-3.10 (m, 4H), 3.40 (m, 3H), 4.25 (m, 1H), 4.40-4.60 (m,1H), 4.82 (t, 1H, J=4 Hz), 7.10 (m, 5H), 7.44 (m, 2H), 7.60 (s, 1H),7.65 (m, 1H), 8.30 (d, 1H, J=7 Hz); MS (ESI) m/z 430 (M+H)⁺.

Example 584-chloro-2-fluoro-N-(2-fluorophenyl)-5-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide

Step A:

To 2-chloro-5-(chlorosulfonyl)-4-fluorobenzoic acid (1.092 g, 4.0 mmol)was added dichloromethane (10 mL), oxalyl chloride (2.8 mL) and onesmall drop of N,N-dimethylformamide. The mixture was stirred at roomtemperature overnight. The mixture was then concentrated to give2-chloro-5-(chlorosulfonyl)-4-fluorobenzoyl chloride which was usedwithout additional purification.

To crude 2-chloro-5-(chlorosulfonyl)-4-fluorobenzoyl chloride (4 mmol)in anhydrous dichloromethane (100 mL) was added(S)-octahydropyrrolo[1,2-a]pyrazine (0.505 g, 4 mmol) in dichloromethane(10 mL) slowly over 10 minutes at room temperature. Then sodiumcarbonate (0.933 g, 8.8 mmol) was added. The mixture was stirred at roomtemperature overnight. Then dichloromethane was removed by concentrationin vacuo, and 2-fluoroaniline (4.44 g, 40 mmol) in dichloromethane (30mL) was added. The mixture was stirred at room temperature for 4 days.At that time, sodium carbonate (0.42 g, 4 mmol) and methanol (20 mL)were added, the mixture was stirred for 30 minutes, then filtered, andconcentrated. The residue was purified by chromatography on silica gel(ethyl acetate, then methanol/ethyl acetate=1:15) to give the titledcompound: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.20-1.38 (m, 1H), 1.60-2.20(m, 7H), 2.80-3.40 (m, 4H), 4.40-4.60 (m, 1H), 7.20 (m, 4H), 7.60 (m,1H), 7.88 (m, 1H), 10.60 (br s, 1H); MS (ESI) m/z 456 (M+H)⁺.

Step B:

The HCl salt (1.0 equiv.) was prepared according to the procedure forExample 1 Step B: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.60-2.20 (m, 5H),2.80-4.00 (m, 7H), 4.60-4.80 (m, 1H), 7.15-7.30 (m, 4H), 7.75-7.97 (m,2H), 10.65 (br s, 1H), 11.60 (m, 1H); MS (ESI) m/z 456 (M+H)⁺.

Example 594-chloro-N-(3,3-diphenylpropyl)-2-fluoro-5-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide

The titled compound was prepared using the procedure described inExample 58 substituting 3,3-diphenylpropan-1-amine (1 equivalent) for2-fluoroaniline: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.21 (m, 2H), 1.56 (m,1H), 1.66 (m, 2H), 1.78 (m, 2H), 2.04 (m, 4H), 2.83 (m, 3H), 2.99 (m,2H), 3.98 (m, 1H), 4.52 (m, 1H), 7.14 (m, 2H), 7.23 (m, 8H), 7.64 (m,1H), 7.83 (m, 1H), 8.22 (m, 1H); MS (ESI) m/z 557 (M+H)⁺.

Example 603-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylsulfonyl]-N-[(1R,2S)-2-phenylcyclopropyl]benzamide

The titled compound was prepared using the procedure described inExample 51 substituting (1R,2S)-2-phenylcyclopropanamine for1-(bis(4-fluorophenyl)methyl)piperazine: ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.22 (m, 2H), 1.37 (m, 1H), 1.60 (m, 2H), 1.77 (m, 1H), 1.97 (m, 3H),2.13 (m, 2H), 2.32 (m, 1H), 2.97 (m, 3H), 3.60 (m, 1H), 3.76 (m, 1H),7.17 (m, 3H), 7.29 (m, 2H), 7.77 (m, 1H), 7.89 (m, 1H), 8.18 (m, 2H),9.15 (m, 1H); (ESI) m/z 426 (M+H)⁺.

Example 613-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]-N-[(1R,2S)-2-phenylcyclopropyl]benzenesulfonamide

The titled compound was prepared using the procedure described inExample 4 Step A substituting (1R,2S)-2-phenylcyclopropanamine (1equivalent) for 2,6-difluoroaniline: ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.11 (m, 3H), 1.64 (m, 3H), 1.86 (m, 3H), 2.05 (m, 2H), 2.27 (m, 1H),2.83 (m, 2H), 3.00 (m, 2H), 4.50 (m, 1H), 6.90 (m, 2H), 7.12 (m, 1H),7.19 (m, 2H), 7.67 (m, 2H), 7.72 (m, 1H), 7.83 (m, 1H), 8.28 (m, 1H);(ESI) m/z 426 (M+H)⁺.

Example 624-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]-N-[(1S)-2-hydroxy-1-phenylethyl]benzenesulfonamide

Oxalyl chloride (2.2 mL) was added to a mixture of4-(chlorosulfonyl)benzoic acid (0.662 g, 3.0 mmol) in anhydrousdichloromethane (25 mL) followed by one small drop ofN,N-dimethylformamide. The mixture was stirred at room temperatureovernight. Then the mixture was then concentrated to provide4-(chlorosulfonyl)benzoyl chloride which was used without additionalpurification.

To 4-(chlorosulfonyl)benzoyl chloride (3 mmol) in anhydrousdichloromethane (100 mL) was slowly added over 10 minutes(R)-octahydropyrrolo[1,2-a]pyrazine (0.379 g, 3 mmol) at roomtemperature in dichloromethane (4 mL). Then sodium carbonate (0.954 g, 9mmol) was added. The mixture was stirred at room temperature overnight.Then the reaction mixture was concentrated to provide4-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonylchloride which was used without additional purification.

Then (S)-2-amino-2-phenylethanol (0.494 g, 3.6 mmol) indichloromethane/NA-dimethylformamide (5:1, 40 mL) was added to the crude4-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonylchloride. The mixture was stirred at room temperature for 3 days, thensodium carbonate (0.21 g, 2 mmol) and methanol (10 mL) were added. Themixture was stirred for an additional 30 minutes, then the reactionmixture was filtered, and the filtrate was concentrated. The residue waspurified by chromatography on silica gel (ethyl acetate/methanol=10:1)to give the titled compound: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.35 (m,1H), 1.60-2.10 (m, 6H), 2.90-3.20 (m, 4H), 3.30-3.50 (m, 3H), 4.30 (m,1H), 4.50 (m, 1H), 4.85 (m, 1H), 7.10 (m, 5H), 7.30 (m, 2H), 7.61 (m,2H), 8.30 (br s, 1H); MS (EST) m/z 430 (M+H)⁺.

Example 63(8aR)-2-[2-chloro-5-(2,3-dihydro-1H-indol-1-ylsulfonyl)-4-fluorobenzoyl]octahydropyrrolo[1,2-a]pyrazine

The titled compound was prepared using the procedure described inExample 58 Step A substituting (R)-octahydropyrrolo[1,2-a]pyrazine for(S)-octahydropyrrolo[1,2-a]pyrazine and substituting indoline for2-fluoroaniline: ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.20 (m, 1H), 1.35 (m,1H), 1.60-2.20 (m, 7H), 2.70-2.90 (m, 2H), 3.00-3.10 (m, 3H), 4.05 (m,2H), 4.40-4.60 (m, 1H), 7.00 (m, 1H), 7.18 (m, 1H), 7.21 (m, 1H), 7.36(m, 1H), 7.90 (m, 2H); MS (ESI) m/z 463 (M+H)⁺.

Example 642,4-dichloro-N-(2-fluorophenyl)-5-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide

Step A:

To ethyl 2,4-dichloro-5-(chlorosulfonyl)benzoate (1 g, 3.15 mmol) inN,N-dimethylacctamide (10.5 mL) was added 2-fluoroaniline (1.215 mL,12.60 mmol) dropwise over 1 minute at room temperature. The mixture wasstirred at room temperature for 1 hour, and then it was diluted withethyl acetate (35 mL). The organic solution was washed with 1 N HCl(2×13 mL) and saturated NaCl (13 mL). The organic layer wasconcentrated, ethanol (38 mL) was added, and the mixture concentrated togive ethyl 2,4-dichloro-5-{[(2-fluorophenyl)amino]sulfonyl}benzoate.

Step B:

To the product of Step A was added ethanol (8 mL) followed by a solutionof NaOH (0.378 g, 9.45 mmol) in water (8 mL). The reaction was stirredat ambient temperature for 45 minutes. To the mixture was added 1 N HCl(23 mL), and the mixture was stirred overnight. The solids werecollected by filtration, washed with water (1×5 mL), and dried by vacuumfiltration to give2,4-dichloro-5-{[(2-fluorophenyl)amino]sulfonyl}benzoic acid: ¹H NMR(400 MHz, DMSO-d₆) δ ppm 13.50 (bs, 1H), 10.30 (bs, 1H), 8.22 (s, 1H),8.04 (s, 1H), 7.28-7.11 (m, 4H); MS (ESI) m/z 362.3 (M−H)⁻.

Step C:

To 2,4-dichloro-5-{[(2-fluorophenyl)amino]sulfonyl}benzoic acid (800 mg,2.197 mmol) and2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (919 mg, 2.416 mmol) in 2-methyltetrahydrofuran(15 mL) was added (R)-octahydropyrrolo[1,2-a]pyrazine (388 mg, 3.08mmol). The reaction was stirred at room temperature for 45 minutes atwhich time N,N-dimethylacetamide (1 mL) was added. The reaction wasstirred for an additional 45 minutes and N,N-dimethylacetamide (3 mL)was added. The reaction was stirred for an addition 2.5 hours, dilutedwith 2-methyltetrahydrofuran (15 mL), and washed with a solution of 6%sodium bicarbonate and 6% brine (2×15 mL). The aqueous layers werecombined and re-extracted with 2-methyltetrahydrofuran (15 mL). Theorganic layer was washed with saturated brine (4×25 mL), dried overMgSO₄, and concentrated. The residue was taken up in ethanol (20 mL) andreconcentrated to give the title compound.

Step D:

To the product of Step C was added ethanol (25 mL) and then concentratedHCl (0.96 g, 2.64 mmol) in ethanol (1 mL) dropwise over 1 minute. Themixture was stirred at ambient temperature overnight and filtered. Theproduct was washed with ethanol and dried in a vacuum oven at roomtemperature to yield the title compound as the hydrochloride salt: ¹HNMR (400 MHz, DMSO-d₆) δ ppm 11.3-10.9 (m, 1H), 10.6 (bs, 1H), 8.1-7.2(m, 2H), 7.3-7.05 (m, 4H), 4.82 (bs d, J=13.45, 1H), 4.0-2.8 (m, 8H),2.33-1.48 (m, 4H); MS (ESI) m/z 472 (M+H)⁺. Diffraction patterns werecollected at ambient conditions in reflection mode using Cu-Kα1(λ=1.54060 Å) radiation. The diffractometer is equipped with a positionsensitive detector that is calibrated at 1 degree intervals using thedirect beam. Calibration is verified with a NIST standard. Maincharacteristic diffraction peak positions (degrees 2-theta +0.1) basedon a diffraction pattern collected under aforementioned conditions areas follows: 7.9, 14.1, 15.4, 15.8, 20.4, 22.1, 25.8

Example 65N-{2-fluoro-5-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide

Step A:

To 3-amino-4-fluorobenzoic acid (0.621 g, 4 mmol) and1-hydroxybenzotriazole hydrate (0.613 g, 4 mmol) indichloromethane/N,N-dimethylformamide (10:1, 60 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC, 0.621 g, 4 mmol).After 5 minutes, (R)-octahydropyrrolo[1,2-a]pyrazine (0.505 g, 4 mmol)in dichloromethane (1 mL) was added. The mixture was stirred at roomtemperature overnight. Then the mixture was concentrated. The residuewas purified by chromatography on silica gel (dichloromethane, thenmethanol/dichloromethane=1:10) to give(R)-(3-amino-4-fluorophenyl)(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methanone:¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.25 (m, 1H), 1.60-2.10 (m, 6H),2.70-3.10 (m, 4H), 3.55-3.70 (m, 1H), 4.40-4.60 (m, 1H), 5.30 (s, 2H),6.50 (m, 1H), 6.77 (m, 1H), 7.00 (m, 1H); MS (ESI) m/z 264 (M+H)⁺.

Step B:

To(R)-(3-amino-4-fluorophenyl)(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methanone(79 mg, 0.3 mmol) and sodium carbonate (64 mg, 0.6 mmol) inN,N-dimethylformamide (1 mL) was added3-(trifluoromethyl)benzene-1-sulfonyl chloride (88 mg, 0.36 mmol) indichloromethane (1 mL), and the mixture was stirred at room temperaturefor 18 hours. Then ethyl acetate was added, and the mixture was washedwith water (2×10 mL). The organic phase was dried over sodium sulfateand concentrated. The residue was purified by chromatography on silicagel (methanol/dichloromethane=1:15) to give the titled compound: ¹H NMR(500 MHz, DMSO-d₆) δ ppm 1.25 (m, 1H), 1.60-2.20 (m, 6H), 2.70-3.10 (m,5H), 4.35-4.55 (m, 1H), 7.22 (m, 3H), 7.82 (m, 1H), 8.00 (m, 3H); MS(ESI) m/z 472 (M+H)⁺.

Example 664-chloro-2-fluoro-N-(2-fluorophenyl)-5-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]-N-methylbenzenesulfonamide

The titled compound was prepared using the procedure described inExample 58 Step A substituting (R)-octahydropyrrolo[1,2-a]pyrazine for(S)-octahydropyrrolo[1,2-a]pyrazine and substituting2-fluoro-N-methylaniline for 2-fluoroaniline: ¹H NMR (500 MHz, DMSO-d₆)δ ppm 1.18-1.35 (m, 1H), 1.60-2.10 (m, 7H), 2.70-3.25 (m, 4H), 3.30 (s,3H), 4.40-4.58 (m, 1H), 7.20-7.55 (m, 4H), 7.58 (m, 1H), 7.98 (m, 1H);MS (ESI) m/z 470 (M+H)⁺.

Example 67(8aR)-2-(2-chloro-4-fluoro-5-{[4-(4-fluorophenyl)piperazin-1-yl]sulfonyl}benzoyl)octahydropyrrolo[1,2-a]pyrazine

The titled compound was prepared using the procedure described inExample 58 Step A substituting (R)-octahydropyrrolo[1,2-a]pyrazine for(S)-octahydropyrrolo[1,2-a]pyrazine and substituting1-(4-fluorophenyl)piperazine for 2-fluoroaniline: ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.21 (m, 1H), 1.56 (m, 1H), 1.66 (m, 3H), 2.88 (m, 3H),2.98 (m, 4H), 3.16 (m, 4H), 3.23 (m, 4H), 4.54 (m, 1H), 6.95 (m, 2H),7.05 (m, 2H), 7.76 (m, 1H), 7.93 (m, 1H); MS (ESI) m/z 526 (M+H)⁺.

Example 68N-{2-chloro-5-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]phenyl}-4-fluorobenzamide

Step A:

(R)-(3-Amino-4-chlorophenyl)(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methanonewas prepared using the procedure described in Example 65 Step Asubstituting 3-amino-4-chlorobenzoic acid for 3-amino-4-fluorobenzoicacid: ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.30 (m, 1H), 1.60-2.10 (m, 6H),2.70-3.10 (m, 4H), 3.55-3.70 (m, 1H), 4.40-4.60 (m, 1H), 5.50 (s, 2H),6.49 (m, 1H), 6.76 (s, 1H), 7.21 (m, 1H); MS (ESI) m/z 280 (M+H)⁺.

Step B:

The titled compound was prepared using the procedure described inExample 65 Step B substituting(R)-(3-amino-4-chlorophenyl)(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methanonefor(R)-(3-amino-4-fluorophenyl)(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methanoneand substituting 4-fluorobenzoyl chloride for3-(trifluoromethyl)benzene-1-sulfonyl chloride: ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.30 (m, 1H), 1.60-2.10 (m, 6H), 2.80-3.20 (m, 4H),3.55-3.68 (m, 1H), 4.45-4.55 (m, 1H), 7.30 (m, 1H), 7.40 (m, 2H), 7.62(m, 2H), 8.08 (m, 2H), 10.20 (s, 1H); MS (ESI) m/z 402 (M+H)⁺.

Example 69N-{3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]phenyl}-N-methyl-3-(trifluoromethyl)benzenesulfonamide

Step A:

(R)-(3-Amino-4-methylphenyl)(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methanonewas prepared using the procedure described in Example 65 Step Asubstituting 3-(methylamino)benzoic acid for 3-amino-4-fluorobenzoicacid: ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.25 (m, 1H), 1.60-1.85 (m, 4H),2.00 (m, 2H), 2.65 (d, 3H, J=6 Hz), 2.70-3.10 (m, 4H), 3.56-3.70 (m,1H), 4.40-4.55 (m, 1H), 5.82 (m, 1H), 6.48 (m, 2H), 6.58 (m, 1H), 7.11(m, 1H); MS (ESI) m/z 260 (M+H)⁺.

Step B:

The title compound was prepared using the procedure described in Example65 Step B substituting(R)-(3-amino-4-methylphenyl)(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methanonefor(R)-(3-amino-4-fluorophenyl)(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methanone:¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.29 (m, 1H), 1.65-2.10 (m, 6H),2.75-3.05 (m, 4H), 3.20 (s, 3H), 3.40-3.50 (m, 1H), 4.40-4.55 (m, 1H),7.10-7.25 (m, 2H), 7.33 (m, 1H), 7.42 (m, 1H), 7.62 (m, 1H), 7.82 (m,2H), 8.15 (m, 1H); MS (ESI) m/z 468 (M+H)⁺.

Example 704-chloro-N-(2,2-diphenylethyl)-2-fluoro-5-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide

The titled compound was prepared using the procedure described inExample 58 Step A substituting (R)-octahydropyrrolo[1,2-a]pyrazine for(S)-octahydropyrrolo[1,2-a]pyrazine and substituting2,2-diphenylethanamine for 2-fluoroaniline: ¹H NMR (400 MHz, DMSO-d₆) δppm 1.20 (m, 1H), 1.56 (m, 1H), 1.67 (m, 3H), 2.89 (m, 3H), 2.97 (m,4H), 3.56 (m, 2H), 4.12 (m, 1H), 4.53 (m, 1H), 7.11 (m, 10H), 7.66 (m,2H), 8.28 (m, 1H); MS (ESI) m/z 543 (M+H)⁺.

Example 71N-{2-chloro-4-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]phenyl}-4-fluorobenzamide

Step A:

(R)-(4-Amino-3-chlorophenyl)(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methanonewas prepared using the procedure described in Example 65 Step Asubstituting 4-amino-3-chlorobenzoic acid for 3-amino-4-fluorobenzoicacid: ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.28 (m, 1H), 1.70 (m, 4H), 2.00(m, 2H), 2.65 (m, 1H), 3.00 (m, 3H), 4.00-4.20 (m, 2H), 5.77 (s, 2H),6.79 (d, 1H, J=8 Hz), 7.09 (d, 1H, J=8 Hz), 7.22 (s, 1H); MS (ESI) m/z280 (M+H)⁺.

Step B:

The titled compound was prepared using the procedure described inExample 65 Step B substituting(R)-(4-amino-3-chlorophenyl)(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methanonefor(R)-(3-amino-4-fluorophenyl)(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methanoneand substituting 4-fluorobenzoyl chloride for3-(trifluoromethyl)benzene-1-sulfonyl chloride: ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.30 (m, 1H), 1.60-2.06 (m, 6H), 2.80-3.20 (m, 4H),3.50-3.62 (m, 1H), 4.40-4.60 (m, 1H), 7.39 (m, 3H), 7.57 (s, 1H), 7.65(m, 1H), 8.05 (m, 2H), 10.18 (s, 1H); MS (ESI) m/z 402 (M+H)⁺.

Example 72N-{4-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]-2-methylphenyl}-2-naphthamide

The titled compound was prepared using the procedure described inExample 65 substituting 4-amino-3-methylbenzoic acid for3-amino-4-fluorobenzoic acid in Step A and substituting 2-naphthoylchloride for 3-(trifluoromethyl)benzene-1-sulfonyl chloride in Step B:¹H NMR (500 MHz, DMSO-d₆) ppm 1.30 (m, 1H), 1.60-2.10 (m, 6H), 2.33 (s,3H), 2.80-3.20 (m, 4H), 3.58-3.70 (m, 1H), 4.45-4.55 (m, 1H), 7.22 (m,1H), 7.36 (m, 1H), 7.50 (m, 1H), 7.62 (m, 2H), 8.10 (m, 4H), 8.60 (s,1H), 10.15 (s, 1H); MS (ESI) m/z 414 (M+H)⁺.

Example 733,5-dichloro-N-{2-fluoro-5-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]phenyl}benzamide

The titled compound was prepared using the procedure described inExample 65 Step B substituting 3,5-dichlorobenzoyl chloride for3-(trifluoromethyl)benzene-1-sulfonyl chloride: ¹H NMR (500 MHz,DMSO-d₆) ppm 1.30 (m, 1H), 1.60-2.20 (m, 6H), 2.80-3.20 (m, 4H),3.55-3.70 (m, 1H), 4.40-4.58 (m, 1H), 7.36 (m, 1H), 7.40 (m, 1H), 7.67(m, 1H), 7.91 (s, 1H), 8.00 (s, 2H), 10.45 (s, 1H); MS (ESI) m/z 436(M+H)⁺.

Example 74N-benzhydryl-4-chloro-2-fluoro-5-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide

The titled compound was prepared using the procedure described inExample 58 Step A substituting (R)-octahydropyrrolo[1,2-a]pyrazine for(S)-octahydropyrrolo[1,2-a]pyrazine and substituting diphenylmethanaminefor 2-fluoroaniline: ¹H NMR (400 MHz, DMSO-d₆) ppm 1.05 (m, 1H), 1.33(m, 1H), 1.67 (m, 2H), 1.93 (m, 5H), 2.94 (m, 3H), 4.33 (m, 1H), 4.61(m, 1H), 7.22 (m, 10H), 7.46 (m, 1H), 7.61 (m, 1H), 9.41 (m, 1H); MS(ESI) m/z 529 (M+H)⁺.

Example 75N-{2-chloro-4-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]phenyl}-2,2-diphenylacetamide

The titled compound was prepared using the procedure described inExample 65 substituting 4-amino-3-chlorobenzoic acid for3-amino-4-fluorobenzoic acid in Step A and substituting2,2-diphenylacetyl chloride for 3-(trifluoromethyl)benzene-1-sulfonylchloride in Step B: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.30 (m, 1H),1.60-2.10 (m, 6H), 2.80-3.20 (m, 4H), 3.50-3.60 (m, 1H), 4.40-4.55 (m,1H), 5.45 (s, 1H), 7.25-7.40 (m, 11H), 7.52 (s, 1H), 7.82 (m, 1H), 10.00(s, 1H); MS (ESI) m/z 474 (M+H)⁺.

Example 76N-{2-chloro-4-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]phenyl}-2-naphthamide

The titled compound was prepared using the procedure described inExample 65 substituting 4-amino-3-chlorobenzoic acid for3-amino-4-fluorobenzoic acid in Step A and substituting 2-naphthoylchloride for 3-(trifluoromethyl)benzene-1-sulfonyl chloride in Step B:¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.30 (m, 1H), 1.60-2.10 (m, 6H),2.80-3.20 (m, 4H), 3.55-3.70 (m, 1H), 4.45-4.55 (m, 1H), 7.42 (m, 1H),7.60-7.75 (m, 4H), 8.08 (m, 4H), 8.62 (s, 1H), 10.30 (s, 1H); MS (ESI)m/z 434 (M+H)⁺.

Example 77N-{3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]phenyl}-N-isopropyl-3-(trifluoromethyl)benzenesulfonamide

Step A:

Potassium phosphate (1.38 g, 6.5 mmol), palladium(II) acetate (56 mg,0.25 mmol), and(R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyl-di-tert-butylphosphine(139 mg, 0.25 mmol) were combined in a microwave tube under nitrogen.Ethyl 3-bromobenzoate (1.145 g, 5 mmol) in dimethoxyethane (2 mL) andisopropylamine (385 mg, 6.5 mmol) in dimethoxyethane (2 mL) were added.The tube was filled with nitrogen again. The tube was then capped, andthe reaction mixture was heated in a microwave oven (Biotage Initiator™2.0, 0 to 100 watts) with stirring at 160° C. for 70 minutes. Thendichloromethane was added, and the crude mixture was filtered. Thefiltrate was concentrated. The residue was purified by chromatography onsilica gel (hexane/ethyl acetate=7:1) to give ethyl3-(isopropylamino)benzoate.

Step B:

To ethyl 3-(isopropylamino)benzoate (540 mg, 2.412 mmol in pyridine (0.7mL) was added 3-(trifluoromethyl)benzene-1-sulfonyl chloride (1.08 g,4.43 mmol), and the mixture was stirred at 90° C. for 18 hours. Themixture was diluted with ethyl acetate (60 mL) and washed with water(3×15 mL). The organic phase was dried over sodium sulfate andconcentrated. The residue was purified by chromatography on silica gel(hexane/ethyl acetate=7:1) to give3-(N-isopropyl-3-(trifluoromethyl)phenylsulfonamido)benzoate: ¹H NMR(300 MHz, CDCl₃) δ ppm 1.08 (d, 6H, J=8 Hz), 1.38 (t, 3H, J=8 Hz), 4.38(t, 2H, J=8 Hz), 4.62 (m, 1H), 7.24 (m, 1H), 7.45 (m, 1H), 7.62 (m, 2H),7.82 (m, 1H), 7.95 (m, 2H), 8.15 (m, 1H); MS (ESI) m/z 416 (M+H)⁺.

Step C:

To ethyl 3-(N-isopropyl-3-(tri fluoromethyl)phenylsulfonamido)benzoate(330 mg, 0.794 mmol) in ethanol (5 mL) was added 2 N KOH solution (2.4mL). The mixture was stirred at room temperature for 3 days, and then 4N HCl solution (1.3 mL) was added. The mixture was concentrated untilthe water was gone. Then dichloromethane/methanol (50:1, 50 mL) wasadded, the solution was filtered, and the filtrate was concentrated togive 3-(N-isopropyl-3-(trifluoromethyl)phenylsulfonamido)benzoic acid:¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.00 (d, 6H, J=8 Hz), 4.62 (m, 1H), 7.30(m, 1H), 7.45 (s, 1H), 7.60 (m, 1H), 7.80-8.10 (m, 5H), 13.18 (br s,1H); MS (ESI) m/z 416 (M−H)⁻.

Step D:

To a mixture of3-(N-isopropyl-3-(trifluoromethyl)phenylsulfonamido)benzoic acid (155mg, 0.4 mmol) and 1-hydroxybenzotriazole hydrate (61 mg, 0.4 mmol) indichloromethane/N,N-dimethylformamide (4:1, 6 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC, 62 mg, 0.4 mmol) indichloromethane (1 mL). After 5 minutes,(R)-octahydropyrrolo[1,2-a]pyrazine (50 mg, 0.4 mmol) in dichloromethane(1 mL) was added. The mixture was stirred at room temperature overnight.Then the mixture was concentrated. The residue was diluted with ethylacetate (100 mL), washed with water (2×20 mL), dried over sodiumsulfate, and concentrated. The residue was purified by chromatography onsilica gel (dichloromethane, then methanol/dichloromethane=1:12) to givethe titled compound: ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.00 (d, 6H, J=8Hz), 1.35 (m, 1H), 1.65-2.10 (m, 6H), 2.80-3.05 (m, 4H), 3.45-3.55 (m,1H), 4.40-4.50 (m, 1H), 4.60 (m, 1H), 6.98 (s, 1H), 7.15 (m, 1H), 7.50(m, 2H), 7.88 (m, 2H), 8.10 (m, 2H); MS (ESI) m/z 496 (M+H)⁺.

Example 78N-{2-chloro-5-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]phenyl}-2,2-diphenylacetamide

The titled compound was prepared using the procedure described inExample 65 substituting 3-amino-4-chlorobenzoic acid for3-amino-4-fluorobenzoic acid in Step A and substituting2,2-diphenylacetyl chloride for 3-(trifluoromethyl)benzene-1-sulfonylchloride in Step B: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.30 (m, 1H),1.60-2.10 (m, 6H), 2.80-3.20 (m, 4H), 3.55-3.65 (m, 1H), 4.40-4.55 (m,1H), 5.42 (s, 1H), 7.20-7.40 (m, 11H), 7.60 (m, 1H), 7.77 (s, 1H), 10.00(s, 1H); MS (ESI) m/z 474 (M+H)⁺.

Example 79N-benzhydryl-N-{2-chloro-5-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]phenyl}amine

The titled compound was prepared using the procedure described inExample 65 substituting 3-amino-4-chlorobenzoic acid for3-amino-4-fluorobenzoic acid in Step A and substituting(bromomethylene)dibenzene for 3-(trifluoromethyl)benzene-1-sulfonylchloride in Step B. In this instance, the Step B reaction was performedwith heating in a microwave oven (Biotage Initiator™ 2.0, 0 to 100watts) at 120° C. for 40 minutes: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.10(m, 1H), 1.50-2.00 (m, 6H), 2.40-2.90 (m, 4H), 3.20 (m, 1H), 4.35-4.50(m, 1H), 5.43 (m, 1H), 5.82 (m, 1H), 6.50 (s, 1H), 6.60 (m, 1H),7.25-7.55 (m, 11H); MS (ESI) m/z 446 (M+H)⁺.

Example 80N-benzhydryl-N-{3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]phenyl}amine

The titled compound was prepared using the procedure described inExample 65 substituting 3-aminobenzoic acid for 3-amino-4-fluorobenzoicacid in Step A and substituting (bromomethylene)dibenzene for3-(trifluoromethyl)benzene-1-sulfonyl chloride in Step B. In thisinstance, the Step B reaction was performed with heating in a microwaveoven (Biotage Initiator™ 2.0, 0 to 100 watts) at 120° C. for 40 minutes:¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.20 (m, 1H), 1.60-2.00 (m, 6H),2.60-2.95 (m, 4H), 3.40 (m, 1H), 4.35-4.50 (m, 1H), 5.64 (m, 1H), 6.45(m, 1H), 6.55 (s, 1H), 6.60 (m, 1H), 6.76 (m, 1H), 7.09 (m, 1H),7.20-7.45 (m, 10H); MS (ESI) m/z 412 (M+H)⁺.

Example 813-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylsulfonyl]-N-[(1S)-2-hydroxy-1-phenylethyl]benzamide

The titled compounds was prepared using the procedure described inExample 1 Step A substituting (S)-2-amino-2-phenylethanol for(R)-octahydropyrrolo[1,2-a]pyrazine and substituting(R)-octahydropyrrolo[1,2-a]pyrazine for 4-(trifluoromethyl)aniline: ¹HNMR (500 MHz, DMSO-d₆) δ ppm 1.20 (m, 1H), 1.60 (m, 2H), 1.80 (m, 1H),1.90-2.08 (m, 3H), 2.15 (m, 1H), 2.35 (m, 1H), 2.90 (m, 1H), 2.98 (m,1H), 3.60-3.80 (m, 4H), 5.00 (m, 1H), 5.10 (m, 1H), 7.20-7.40 (m, 5H),7.78 (m, 1H), 7.95 (m, 1H), 8.22 (m, 2H), 9.08 (m, 1H); MS (ESI) m/z 430(M+H)⁺.

Example 82N-benzhydryl-2-chloro-4-fluoro-5-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylsulfonyl]benzamide

The titled compound was prepared using the procedure described inExample 58 Step A substituting diphenylmethanamine for(S)-octahydropyrrolo[1,2-a]pyrazine and substituting(S)-octahydropyrrolo[1,2-a]pyrazine for 2-fluoroaniline: ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.24 (m, 1H), 1.63 (m, 2H), 1.79 (m, 1H), 1.94 (m,1H), 2.07 (m, 3H), 2.33 (m, 1H), 2.62 (m, 1H), 2.96 (m, 2H), 3.63 (m,1H), 3.77 (m, 1H), 6.31 (m, 1H), 7.28 (m, 3H), 7.37 (m, 6H), 7.70 (m,1H), 7.81 (m, 1H), 9.59 (m, 1H); MS (ESI) m/z 529 (M+H)⁺.

Example 832-chloro-N-cyclopropyl-4-fluoro-5-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylsulfonyl]benzamide

The titled compound was prepared using the procedure described inExample 58 Step A substituting cyclopropanamine for(S)-octahydropyrrolo[1,2-a]pyrazine and substituting(S)-octahydropyrrolo[1,2-a]pyrazine for 2-fluoroaniline: ¹H NMR (400MHz, DMSO-d₆) δ ppm 0.54 (m, 2H), 0.70 (m, 2H), 1.24 (m, 1H), 1.63 (m,2H), 1.78 (m, 1H), 1.93 (m, 1H), 2.08 (m, 2H), 2.34 (m, 1H), 2.64 (m,1H), 2.80 (m, 1H), 2.97 (m, 2H), 3.65 (m, 1H), 3.78 (m, 1H), 7.72 (m,1H), 7.86 (m, 1H), 8.65 (m, 1H); MS (ESI) m/z 402 (M+H)⁺.

Many variations in the invention suggest themselves to those skilled inthe art in light of the foregoing detailed description. All such obviousvariations are within the full intended scope of the appended claims.

We claim:
 1. A compound of formula (I) or (II),

or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or acombination thereof, wherein one of R¹ and R² is X, and the other of R¹and R² is Y; X is (i) or (ii);

m and n, at each occurrence, are independently 1 or 2; G¹ is azetidinyl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or azepanyl,wherein G¹ is connected through the nitrogen atom of said azetidinyl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or azepanyl; Yis —NR^(c)Ar¹, —NR^(c)Ar²—Ar¹, —NR^(c)CH(Ar¹)₂,—NR^(c)(CR^(a)R^(b))_(p)Ar¹, —NR^(c)(CR^(a)R^(b))_(p)CH(Ar¹)₂,—NR^(c)-G², —NR^(c)-G²-Ar¹, (iii), (iv), (v) or (vi);

Ar¹, at each occurrence, is independently aryl or heteroaryl, whereinsaid aryl and heteroaryl are unsubstituted or substituted with 1, 2, 3,or 4, or 5 substituents selected from alkoxy, alkyl, cyano, haloalkyl,halogen, or —N(alkyl)₂; Ar² is aryl or heteroaryl, wherein said aryl andheteroaryl are unsubstituted or substituted with 1, 2, 3, or 4substituents selected from alkoxy, alkyl, cyano, haloalkyl, or halogen;G² is cycloalkyl; R^(a) and R^(b) are at each occurrence independentlyhydrogen, alkyl, or hydroxyalkyl; R^(c) is hydrogen or alkyl; p is 1, 2,3, or 4; and R³, R⁴, R⁵ and R⁶ are each independently hydrogen, alkoxy,alkyl, or halogen.
 2. The compound according to claim 1 of formula (I)or formula (II), wherein R¹ is X; X is

R² is Y; and Y is NR^(c)Ar¹.
 3. The compound according to claim 2 offormula (I), wherein n is 1; Ar¹ is aryl; and R³, R⁴, R⁵ and R⁶ are eachindependently hydrogen or halogen.
 4. The compound according to claim 1of formula (I) or formula (II), wherein R¹ is X; X is

n is 1; R² is Y; and Y is —NR^(c)CH(Ar¹)₂,—NR^(c)(CR^(a)R^(b))_(p)CH(Ar¹)₂, or (v).


5. The compound according to claim 4 of formula (I), wherein R^(a) andR^(b) are at each occurrence hydrogen; R^(c) is hydrogen; p is 1, 2 or3; Ar¹, at each occurrence, is aryl; and R³, R⁴, R⁵ and R⁶ are eachindependently hydrogen or halogen.
 6. The compound according to claim 1of formula (I) or formula (II), wherein R¹ is X; X is

n is 1; R² is Y; and Y is —NR^(c)Ar²—Ar¹, —NR^(c)(CR^(a)R^(b))_(p)Ar¹,—NR^(c)-G²-Ar¹, (iii), (iv), or (vi).


7. The compound according to claim 6 of formula (I), wherein R^(a) andR^(b) are, at each occurrence, independently hydrogen or hydroxyalkyl;R^(c) is hydrogen; p is 1, 2 or 3; Ar¹ is aryl; Ar² is aryl; G² iscyclopropyl; and R³, R⁴, R⁵ and R⁶ are each independently hydrogen orhalogen.
 8. The compound according to claim 6 of formula (II), whereinR^(a) and R^(b) are, at each occurrence, independently hydrogen orhydroxyalkyl; R^(c) is hydrogen; p is 1, 2 or 3; Ar¹ is aryl; Ar² isaryl; G² is cyclopropyl; and R³, R⁴, R⁵ and R⁶ are each independentlyhydrogen or halogen.
 9. The compound according to claim 1 of formula (I)or formula (II), wherein R¹ is X; and X is


10. The compounds according to claim 9 of formula (I), wherein G¹ ispyrrolidinyl or piperidinyl; R² is Y; Y is NR^(c)Ar¹; R^(c) is hydrogen;and Ar¹ is aryl, wherein said aryl is unsubstituted or substituted with1, 2, or 3 substituents selected from haloalkyl and halogen.
 11. Thecompound according to claim 1 of formula (I) or formula (II), wherein R¹is Y; Y is —NR^(c)CH(Ar¹)₂, —NR^(c)(CR^(a)R^(b))_(p)CH(Ar¹)₂, or (v);

R^(a) and R^(b) at each occurrence are independently hydrogen; R² is X;X is

and n is
 1. 12. The compound according to claim 11 of formula (I),wherein R^(a) and R^(b) are, at each occurrence, hydrogen; p is 1 or 2;Ar¹, at each occurrence, is independently aryl, wherein said aryl isunsubstituted or substituted with 1, 2, 3, or 4, or 5 substituentsselected from alkoxy, alkyl, cyano, haloalkyl, halogen, or —N(alkyl)₂;and R³, R⁴, R⁵ and R⁶ are each independently hydrogen or halogen. 13.The compound according to claim 1 of formula (I) or formula (II),wherein R¹ is Y; Y is —NR^(c)Ar¹, —NR^(c)(CR^(a)R^(b))_(p)Ar¹,—NR^(c)-G², —NR^(c)-G²-Ar¹, (iii), (iv), or (vi);

R² is X; and X is


14. The compound according to claim 13 of formula (I), wherein R¹ is Y;Y is —NR^(c)Ar¹, —NR^(c)(CR^(a)R^(b))_(p)Ar¹, —NR^(c)-G². or—NR^(c)-G²-Ar¹; R^(a) and R^(b) are independently, at each occurrence,hydrogen or hydroxyalkyl; p is 1, 2 or 3; Ar¹, at each occurrence, isindependently aryl, wherein said aryl is unsubstituted or substitutedwith 1, 2, 3, or 4, or 5 substituents selected from alkoxy, alkyl,cyano, haloalkyl, halogen, or —N(alkyl)₂; G² is cycloalkyl, whereincycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; andR³, R⁴, R⁵ and R⁶ are each independently hydrogen or halogen.
 15. Acompound of formula (ITT) or (IV),

or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or acombination thereof, wherein L¹ is C(O) or S(O)₂; R² is X; X is (i) or(ii);

m and n, at each occurrence, are independently 1 or 2; G¹ is azetidinyl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or azepanyl,wherein G¹ is connected through the nitrogen atom of said azetidinyl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or azepanyl; R³,R⁴, R⁵ and R⁶ are each independently hydrogen, alkoxy, alkyl, orhalogen; R⁷ is S(O)₂Ar³, —C(O)Ar³, S(O)₂(CR^(a)R^(b))_(p)Ar³,—C(O)(CR^(a)R^(b))_(p)Ar³, —S(O)₂(CR^(a)R^(b))_(p)CH(Ar³)₂,—C(O)(CR^(a)R^(b))_(p)CH(Ar³)₂, —C(O)CH(Ar³)₂, or —CH(Ar³)₂; Ar³, ateach occurrence, is aryl or heteroaryl, wherein said aryl and heteroarylare unsubstituted or substituted with 1, 2, 3, 4, or 5 substituentsselected from alkoxy, alkyl, cyano, haloalkyl, or halogen; R^(a) andR^(b) are at each occurrence independently hydrogen, alkyl, orhydroxyalkyl; p is 1, 2, 3, or 4; and R^(c)C is hydrogen or alkyl. 16.The compound of claim 15 of formula (III), wherein L¹ is C(O); R² is X;X is (i);

R⁷ is S(O)₂Ar³, —C(O)Ar³, S(O)₂(CR^(a)R^(b))_(p)Ar³, or—C(O)(CR^(a)R^(b))_(p)Ar³ and Ar³, at each occurrence, is aryl, whereinsaid aryl is unsubstituted or substituted with 1, 2, 3, 4, or 5substituents selected from alkoxy, alkyl, cyano, haloalkyl, or halogen.17. The compound of claim 15 of formula (IV), wherein L¹ is C(O); R² isX; X is (i);

R⁷ is S(O)₂Ar³, —C(O)Ar³, S(O)₂(CR^(a)R^(b))_(p)Ar³, or—C(O)(CR^(a)R^(b))_(p)Ar³; and Ar³ is aryl, wherein said aryl isunsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selectedfrom alkoxy, alkyl, cyano, haloalkyl, or halogen.
 18. The compound ofclaim 15 of formula (III), wherein L¹ is C(O); R² is X; X is (i);

R⁷ is —S(O)₂(CR^(a)R^(b))_(p)CH(Ar³)₂, —C(O)(CR^(a)R^(b))_(p)CH(Ar³)₂,—C(O)CH(Ar³)₂, or —CH(Ar³)₂; Ar³, at each occurrence, is aryl, whereinsaid aryl is unsubstituted or substituted with 1, 2, 3, 4, or 5substituents selected from alkoxy, alkyl, cyano, haloalkyl, or halogen;and p is 1, 2, or
 3. 19. The compound of claim 15 of formula (IV),wherein L¹ is C(O); R² is X; X is (i);

R⁷ is —S(O)₂(CR^(a)R^(b))_(p)CH(Ar³)₂, —C(O)(CR^(a)R^(b))_(p)CH(Ar³)₂,—C(O)CH(Ar³)₂, or —CH(Ar³)₂; Ar³, at each occurrence, is aryl, whereinsaid aryl is unsubstituted or substituted with 1, 2, 3, 4, or 5substituents selected from alkoxy, alkyl, cyano, haloalkyl, or halogen;and p is 1, 2, or
 3. 20. The compound according to claim 1 or claim 15or a pharmaceutically acceptable salt thereof, selected from the groupconsisting of:3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]-N-[4-(trifluoromethyl)phenyl]benzenesulfonamide;N-(2-fluorophenyl)-3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;N-(3-fluorophenyl)-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;N-(2,6-difluorophenyl)-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;N-(4-fluorophenyl)-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]-N-[3-(trifluoromethyl)phenyl]benzenesulfonamide;N-(3-fluorophenyl)-3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]-N-[4-(trifluoromethyl)phenyl]benzenesulfonamide;N-(2-chlorophenyl)-3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;N-(2-chlorophenyl)-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;N-(2,3-difluorophenyl)-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;N-(2,5-difluorophenyl)-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;N-(2,6-difluorophenyl)-3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;N-(2,3-difluorophenyl)-3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;N-(2,5-difluorophenyl)-3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;N-(2,4-difluorophenyl)-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;N-(2-fluorophenyl)-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;N-(2,4-difluorophenyl)-3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]-N-[2-(trifluoromethyl)phenyl]benzenesulfonamide;4-chloro-2-fluoro-N-(2-fluorophenyl)-5-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;N-(3-chlorophenyl)-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;(8aR)-2-[3-({4-[bis(4-fluorophenyl)methyl]piperazin-1-yl}sulfonyl)benzoyl]octahydropyrrolo[1,2-a]pyrazine;(8aS)-2-[3-({4-[bis(4-fluorophenyl)methyl]piperazin-1-yl}sulfonyl)benzoyl]octahydropyrrolo[1,2-a]pyrazine;(8aR)-2-{3-[(4-benzhydrylpiperazin-1-yl)sulfonyl]benzoyl}octahydropyrrolo[1,2-a]pyrazine;N-(3-chlorophenyl)-3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;N-(2,2-diphenylethyl)-3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]-N-[2-(trifluoromethyl)phenyl]benzenesulfonamide;(8aS)-2-{3-[(4-benzhydrylpiperazin-1-yl)sulfonyl]benzoyl}octahydropyrrolo[1,2-a]pyrazine;N-(3,3-diphenylpropyl)-3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzene sulfonamide;N-(3,3-diphenylpropyl)-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;N-(2,2-diphenylethyl)-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide; 4-chloro-3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]-N-[4-(trifluoromethyl)phenyl]benzenesulfonamide;N-[2-(4-fluorophenyl)ethyl]-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;2-chloro-5-[(8 aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]-N-[4-(trifluoromethyl)phenyl]benzenesulfonamide;(8aS)-2-(3-{[4-(4-fluorophenyl)piperazin-1-yl]sulfonyl}benzoyl)octahydropyrrolo[1,2-a]pyrazine;N-1,1′-biphenyl-2-yl-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;3-(octahydro-2H-pyrido[1,2-a]pyrazin-2-ylcarbonyl)-N-[4-(trifluoromethyl)phenyl]benzenesulfonamide;3-(octahydro-2H-pyrido[1,2-a]pyrazin-2-ylcarbonyl)-N-[3-(trifluoromethyl)phenyl]benzenesulfonamide;N-(2-fluorophenyl)-3-(octahydro-2H-pyrido[1,2-a]pyrazin-2-ylcarbonyl)benzenesulfonamide;N-(4-fluorophenyl)-3-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]benzenesulfonamide;N-phenyl-3-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]benzenesulfonamide;3-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]-N-[4-(trifluoromethyl)phenyl]benzenesulfonamide;3-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]-N-[3-(trifluoromethyl)phenyl]benzenesulfonamide;N-(3-fluorophenyl)-3-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]benzenesulfonamide;N-(2-fluorophenyl)-3-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]benzenesulfonamide;3-(1,4′-bipiperidin-1′-ylcarbonyl)-N-(4-fluorophenyl)benzenesulfonamide;3-(1,4′-bipiperidin-1′-ylcarbonyl)-N-(2-fluorophenyl)benzenesulfonamide;3-(1,4′-bipiperidin-1′-ylcarbonyl)-N-(3-fluorophenyl)benzenesulfonamide;3-(1,4′-bipiperidin-1′-ylcarbonyl)-N-[4-(trifluoromethyl)phenyl]benzenesulfonamide;(8aR)-2-{[3-({4-[bis(4-fluorophenyl)methyl]piperazin-1-yl}carbonyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(8aS)-2-{[3-({4-[bis(4-fluorophenyl)methyl]piperazin-1-yl}carbonyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(8aR)-2-({3-[(4-benzhydrylpiperazin-1-yl)carbonyl]phenyl}sulfonyl)octahydropyrrolo[1,2-a]pyrazine;N-(2,2-diphenylethyl)-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylsulfonyl]benzamide;(8aS)-2-({3-[(4-benzhydrylpiperazin-1-yl)carbonyl]phenyl}sulfonyl)octahydropyrrolo[1,2-a]pyrazine;N-(3,3-diphenylpropyl)-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylsulfonyl]benzamide;N-[2-(4-fluorophenyl)ethyl]-3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylsulfonyl]benzamide;3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]-N-[(1S)-2-hydroxy-1-phenylethyl]benzenesulfonamide;4-chloro-2-fluoro-N-(2-fluorophenyl)-5-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;4-chloro-N-(3,3-diphenylpropyl)-2-fluoro-5-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylsulfonyl]-N-[(1R,2S)-2-phenylcyclopropyl]benzamide;3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]-N-[(1R,2S)-2-phenylcyclopropyl]benzenesulfonamide;4-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]-N-[(1S)-2-hydroxy-1-phenylethyl]benzenesulfonamide;(8aR)-2-[2-chloro-5-(2,3-dihydro-1H-indol-1-ylsulfonyl)-4-fluorobenzoyl]octahydropyrrolo[1,2-a]pyrazine;2,4-dichloro-N-(2-fluorophenyl)-5-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;N-{2-fluoro-5-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide;4-chloro-2-fluoro-N-(2-fluorophenyl)-5-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]-N-methylbenzenesulfonamide;(8aR)-2-(2-chloro-4-fluoro-5-{[4-(4-fluorophenyl)piperazin-1-yl]sulfonyl}benzoyl)octahydropyrrolo[1,2-a]pyrazine;N-{2-chloro-5-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]phenyl}-4-fluorobenzamide;N-{3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]phenyl}-N-methyl-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-(2,2-diphenylethyl)-2-fluoro-5-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;N-{2-chloro-4-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]phenyl}-4-fluorobenzamide;N-{4-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]-2-methylphenyl}-2-naphthamide;3,5-dichloro-N-{2-fluoro-5-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]phenyl}benzamide;N-benzhydryl-4-chloro-2-fluoro-5-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonamide;N-{2-chloro-4-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]phenyl}-2,2-diphenylacetamide;N-{2-chloro-4-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]phenyl}-2-naphthamide;N-{3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]phenyl}-N-isopropyl-3-(trifluoromethyl)benzenesulfonamide;N-{2-chloro-5-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]phenyl}-2,2-diphenylacetamide;N-benzhydryl-N-{2-chloro-5-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]phenyl}amine;N-benzhydryl-N-{3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]phenyl}amine;3-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylsulfonyl]-N-[(1S)-2-hydroxy-1-phenylethyl]benzamide;N-benzhydryl-2-chloro-4-fluoro-5-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylsulfonyl]benzamide;and2-chloro-N-cyclopropyl-4-fluoro-5-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylsulfonyl]benzamide.21. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of formula (I) or formula (II) according to claim 1or, formula (III) or formula (IV) according to claim 15 or apharmaceutically acceptable salt thereof, in combination with apharmaceutically acceptable carrier.
 22. A method of treating pain in asubject in need thereof, comprising: administering to the subject atherapeutically suitable amount of a compound of formula (I), formula(II), formula (III), or formula (IV), or a pharmaceutically acceptablesalt thereof, wherein the pain is acute pain, chronic pain, neuropathicpain, inflammatory pain, visceral pain, cancer pain, allodynia,fibromyalgia, sciatica, back pain, and headache pain including migraine,or combinations thereof.
 23. A method of treating disorders of thecentral nervous system in a subject in need thereof, comprising the stepof: administering a therapeutically suitable amount of a compound offormula (I), formula (II), formula (III), or formula (IV), or apharmaceutically acceptable salt thereof, wherein the disorders of thecentral nervous system include stroke, epilepsy, manic depression,bipolar disorders, depression, anxiety, schizophrenia, migraine, andpsychoses; neural degenerative disorders including Alzheimer's disease,AIDS related dementia, Parkinson's disease, neuropathy caused by headinjury, and dementia caused by cerebrovascular disorders; disorders ofthe lower urinary tract including overactive bladder, prostatis,prostadynia, interstitial cystitis, and benign prostatic hyperplasia;disorders caused by psychogenic stress including bronchial asthma,unstable angina, and hypersensitive colon inflammation; cardiovasculardisorders including hypertension, atherosclerosis, heart failure, andcardiac arrhythmias; drug addiction withdrawal symptoms, includingethanol addiction withdrawal symptoms; skin disorders including pruritisand allergic dermatitis, inflammatory bowel disease; cancer; diabetes;and infertility and sexual dysfunction, or combinations thereof.